Clinical Investigations

Effects of Sigh on Regional Lung Strain and Ventilation Heterogeneity in Acute Respiratory Failure Patients Undergoing Assisted Mechanical Ventilation* Tommaso Mauri, MD1,2; Nilde Eronia, MD1; Chiara Abbruzzese, MD3; Roberto Marcolin, MD3; Andrea Coppadoro, MD4; Savino Spadaro, MD5; Nicolo’ Patroniti, MD1,3; Giacomo Bellani, MD, PhD1,3; Antonio Pesenti, MD1,3 Objective: In acute respiratory failure patients undergoing pressure support ventilation, a short cyclic recruitment maneuver (Sigh) might induce reaeration of collapsed lung regions, possibly decreasing regional lung strain and improving the homogeneity of ventilation distribution. We aimed to describe the regional effects of different Sigh rates on reaeration, strain, and ventilation heterogeneity, as measured by thoracic electrical impedance tomography. Design: Prospective, randomized, cross-over study. Setting: General ICU of a single university-affiliated hospital. Patients: We enrolled 20 critically ill patients intubated and mechanically ventilated with Pao2/Fio2 up to 300 mm Hg and positive end-expiratory pressure at least 5 cm H2O (15 with acute *See also p. 2021. 1 Department of Health Science, University of Milan-Bicocca, Monza, Italy. 2 Department of Anesthesia, Critical Care and Pain Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. 3 Department of Emergency Medicine, San Gerardo Hospital, Monza, Italy. 4 Department of Emergency Medicine, A. Manzoni Hospital, Lecco, Italy. 5 Department of Medical Surgical and Experimental Medicine, Section of Anesthesia and Intensive Care, University of Ferrara, Ferrara, Italy. This work was performed in the general ICU of the Department of Emergency Medicine, San Gerardo Hospital, Monza, Italy. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by institutional funding of the Department of Health Science, University of Milan-Bicocca, Monza, Italy, and by an unrestricted research grant from Drager GmbH, Lubeck, Germany, to the Department of Emergency, San Gerardo Hospital, Monza, Italy. The supporting company did not have any formal requirement for financial or technical reports as well as no claim to any intellectual property rights that resulted from the study. The supporting company had no role in study conception, design and conduction, data analysis, and/or writing of the article. Dr. Pesenti’s institution received grant support from Drager Company, Lubeck, Germany. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001083

Critical Care Medicine

respiratory distress syndrome), undergoing pressure support ventilation as per clinical decision. Interventions: Sigh was added to pressure support ventilation as a 35 cm H2O continuous positive airway pressure period lasting 3–4 seconds at different rates (no-Sigh vs 0.5, 1, and 2 Sigh(s)/min). All study phases were randomly performed and lasted 20 minutes. Measurements and Main Results: In the last minutes of each phase, we measured arterial blood gases, changes in end-expiratory lung volume of nondependent and dependent regions, tidal volume reaching nondependent and dependent lung (Vtnondep and Vtdep), dynamic intratidal ventilation heterogeneity, defined as the average ratio of Vt reaching nondependent/Vt reaching dependent lung regions along inspiration (VtHit). With Sigh, oxygenation improved (p < 0.001 vs no-Sigh), end-expiratory lung volume of nondependent and dependent regions increased (p < 0.01 vs noSigh), Vtnondep showed a trend to reduction, and Vtdep significantly decreased (p = 0.11 and p < 0.01 vs no-Sigh, respectively). VtHit decreased only when Sigh was delivered at 0.5/min (p < 0.05 vs no-Sigh), while it did not vary during the other two phases. Conclusions: Sigh decreases regional lung strain and intratidal ventilation heterogeneity. Our study generates the hypothesis that in ventilated acute respiratory failure patients, Sigh may enhance regional lung protection. (Crit Care Med 2015; 43:1823–1831) Key Words: acute lung injury; electrical impedance tomography; lung volume measurements; mechanical ventilation; ventilatorinduced lung injury

A

cute respiratory failure patients undergoing mechanical ventilation present heterogeneous distribution of alveolar collapse across all lung regions (1). Diffuse heterogeneous alveolar collapse increases the regional tidal volume/end-expiratory lung volume (Vt/EELV) ratio (i.e., the regional lung strain) (2) and the structural heterogeneity of the lung (i.e., the presence of lung regions with lower gas/tissue ratio than their neighboring ones) (3, 4). Both strain and heterogeneity are associated with higher risk of ventilator-induced lung injury (VILI) (5). Indeed, higher regional lung strain and heterogeneity (6) might cause www.ccmjournal.org

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Mauri et al

Table 1.

Main Characteristics of the Study Population

Patient No.

Age (Yr)

Sex

Body Mass Index (kg/ m2)

Simplified Acute Physiology Score II

Etiology of Respiratory Failure

1

80

Male

22

55

Infectious/secondary

2

50

Female

46

34

Infectious/secondary

3

78

Male

27

53

Noninfectious/primary

4

72

Male

36

51

Infectious/secondary

5

44

Male

31

29

Noninfectious/primary

6

81

Female

27

45

Infectious/primary

7

81

Female

23

41

Infectious/primary

8

72

Female

25

55

Infectious/secondary

9

45

Female

22

57

Infectious/primary

10

65

Female

27

39

Noninfectious/primary

11

77

Male

24

46

Infectious/primary

12

72

Male

26

58

Infectious/secondary

13

55

Male

26

37

Noninfectious/secondary

14

52

Female

25

43

Noninfectious/primary

15

47

Male

48

30

Infectious/primary

16

65

Female

22

73

Noninfectious/secondary

17

66

Male

29

56

Infectious/primary

18

74

Male

21

49

Infectious/secondary

19

71

Female

29

49

Infectious/secondary

20

65

Female

24

89

Noninfectious/secondary

28 ± 7

49 ± 14

16 infectious, 10 primary

Mean ± sd

66 ± 12

10 Female

See Methods section for details.

overdistension, barotrauma, and inflammation to the already injured as well as to the healthier lung regions (i.e., where EELV is lower and Vt higher, respectively), even in the presence of ventilation settings within protective limits (5–8). Regional strain and heterogeneity might contribute substantially to the high mortality rate of ventilated acute respiratory failure patients (9). Recently, evidence is growing that in patients with acute respiratory failure, after the first 48 hours when deep sedation and paralysis could improve survival (10), the switch from controlled to assisted mechanical ventilation might be associated with several clinical benefits (e.g., reduced muscle weakness, improved hemodynamics, decreased sedation, and early mobilization) (11, 12). However, the effects of assisted ventilation on alveolar collapse and regional strain have not been carefully studied (13). In this study, we reasoned that an assisted ventilation strategy coupling protective settings with reaeration of collapsed lung regions might decrease the regional strain and obtain more homogenous lung structure, thus limiting the risk of VILI. To this end, previous studies showed that in acute respiratory failure patients undergoing assisted protective ventilation, cyclic short recruitment maneuvers (Sigh) improve oxygenation and EELV (14, 15). 1824

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The aim of this study was to verify, in ventilated acute respiratory failure patients undergoing protective assisted ventilation, the regional effects of Sigh on lung strain and heterogeneity. For this purpose, we assessed regional dynamic lung imaging by electrical impedance tomography (EIT): a noninvasive, radiation-free, bedside lung imaging technique, which tracks changes in regional lung impedance, corresponding to changes in regional gas content (16–18). By EIT, we measured the changes induced by Sigh on regional Vt, regional EELV, and the heterogeneity of ventilation distribution. Thus, in this study, we directly assessed regional strain (i.e., regional Vt/EELV ratio) while, based on sound physiological background and previous studies (4), heterogeneity of ventilation distribution (18) was considered close surrogate of regional heterogeneity of lung structure (3). Finally, we delivered Sigh at different mandatory rates in an effort to identify its “minimum effective dose.”

METHODS Study Population We conducted a prospective randomized cross-over study on 20 acute respiratory failure patients admitted to the general September 2015 • Volume 43 • Number 9

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Clinical Investigations

Lung Injury Score

Acute Respiratory Distress Syndrome

Days of Intubation

Dead

Pressure Support (cm H2O)

Positive End-Expiratory Pressure (cm H2O)

Fio2

2

Yes

2

Yes

6

8

0.5

2.75

Yes

3

Yes

14

12

0.45

1.25

No

8

No

10

5

0.4

2.5

Yes

3

Yes

6

10

0.6

1.5

No

1

Yes

8

7

0.4

2.5

Yes

2

Yes

10

8

0.65

2.75

Yes

3

No

8

6

0.55

2.25

Yes

1

No

5

8

0.5

2.25

Yes

2

No

8

8

0.45

2.25

No

10

No

8

10

0.55

2.25

No

2

Yes

10

10

0.65

1.5

Yes

6

No

8

8

0.5

2.25

Yes

37

Yes

12

5

0.5

2

Yes

14

No

8

7

0.4

2.25

Yes

8

No

5

10

0.4

1.75

No

2

No

8

9

0.4

1.75

Yes

4

No

9

10

0.45

2.25

Yes

6

No

2

6

0.35

2.5

Yes

6

No

6

8

0.5

2.5

Yes

2

No

10

8

0.5

2.15 ± 0.4

15 Yes

6 ± 8

7 Yes

8 ± 2

8 ± 2

0.5 ± 0.1

ICU of San Gerardo Hospital, Monza, Italy. Inclusion criteria were intubated patients with Pao2/Fio2 ratio up to 300 mm Hg and positive end-expiratory pressure (PEEP) at least 5 cm H2O undergoing pressure support ventilation (PSV) for less than 72 hours. Institutional ethical committee approved the study, and informed consent was obtained for each patient according to local regulations. Clinical Data At enrollment, we collected physiological and clinical signs of severity. In-hospital mortality was recorded, too. EIT Monitoring EIT dedicated belt was placed around the patient’s chest and connected to a commercial EIT monitor (PulmoVista 500; Dräger Medical GmbH, Lübeck, Germany). EIT data were generated by application of small alternate electrical currents rotating around patient’s thorax and stored for offline analysis, as previously described (16–18). Airway pressure, flow, and volume tracings were continuously recorded. Critical Care Medicine

Study Protocol Baseline PSV was set to obtain protective Vt (i.e., ≈6–8 mL/kg ideal body weight [IBW]) with respiratory rate below 30 breaths/min. PEEP was clinically set with Fio2 to obtain Po2 of 70–100 mm Hg. After 20–30 minutes of clinical stability, Sigh was introduced as a 35-cm H2O continuous positive airway pressure time period, lasting 3–4 seconds. Ventilators were switched to biphasic positive airway pressure (BiPAP) + PSV, and Sighs were performed by means of the higher BiPAP pressure level, as previously described (14). The study consisted of four cross-over randomized phases lasting 20 minutes each. PSV was left unchanged and Sigh rate was set as follows: ●● ●● ●● ●●

Baseline PSV no Sigh (phase Sigh0) Baseline PSV + one Sigh every 2 minutes (Sigh0.5) Baseline PSV + one Sigh per minute (Sigh1) Baseline PSV + one Sigh every 30 seconds (Sigh2)

In summary, PSV was compared with PSV + BiPAP set with a 3- to 4-second inspiratory time and then 120-, 60-, and 30-second expiratory times (Sigh0.5, Sigh1, and Sigh2, respectively). www.ccmjournal.org

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Gas Exchange, Hemodynamics, and Ventilation Data At the end of each phase, we collected arterial and central venous blood gases, we assessed hemodynamics, and we performed end-inspiratory and end-expiratory occlusions between two Sighs, while assuring for patients’ relaxation. Acceptable pauses were obtained in 16 patients (80%), whereas four patients required additional sedation by shortacting drugs (e.g., Propofol 0.1–0.2 mg/kg IBW). Then, from offline analysis of ventilation tracings, we registered spontaneous respiratory rate (RRspont), global Vt, total minute ventilation (MVtot), Sigh volume, MV generated by Sighs (MVSigh: the amount of air expired by the patient after Sigh[s] over a minute), mean airway pressure (mean Paw), end-inspiratory plateau pressure (Pplat), PMusc Index (PMI, an estimate of patients’ inspiratory effort) calculated as PMI = [Pplat – (PEEP + PSV)] (19), and respiratory system static compliance (Crs) calculated as Crs = Vtocclusion/(Pplat – PEEP). Regional EIT Data We defined two same-size contiguous regions of interests from halfway up and down of the imaging field (nondependent [nondep] and dependent [dep], respectively) (18). Then, from offline analyses of average raw EIT data of selected representative tidal breaths, we measured the following: 1. Changes in global and regional EELV (EELVgl, EELVnondep, and EELVdep, respectively) defined as the global and regional change in end-expiratory impedance, considering Sigh0 as baseline, multiplied by the ratio between Vt measured by the ventilator and the global impedance change between end expiration and end inspiration, both taken at Sigh0 (16, 20). As PEEP was not modified and Sigh affected mean Paw only by 1–2 cm H2O, we reasoned that, in our patients, changes of global and regional EELV induced by Sigh corresponded to reaeration of previously collapsed lung areas (i.e., alveolar recruitment) 2. The relative (expressed as percentage) and absolute (expressed in mL) values of Vt reaching nondependent and dependent lung regions (Vt%nondep and Vt%dep; Vtnondep and Vtdep; respectively) 3. The regional Crs values, measured as Vtnondep or Vtdep divided by the difference between end-inspiratory Pplat and PEEP (Crsnondep and Crsdep, respectively). Crsnondep was measured also during Sigh (Crs-Sighnondep) as the gas volume introduced by Sigh into nondependent region divided by the end-inspiratory Sigh pressure (i.e., 35 cm H2O) minus total PEEP. In fact, within each study phase, Crs-Sighnondep values lower than Crsmeasured during tidal breathing could be regarded as a nondep sign of lung hyperdistension induced by Sigh (21) 4. The cumulated lung hyperdistension for each phase measured during tidal ventilation (22). Briefly, the pixel-level hyperdistension during tidal PSV breaths was calculated as follow: Hyperdistension pixel (%) =

(Sigh

0

Sigh 0 Compliance pixel

1826

)

Compliance pixel − Sigh 0.5,1 ,or 2 Compliance pixel × 100

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Then, cumulated hyperdistension for the whole imaging field (1,024 pixels) was computed as follows: Cumulated hyperdistension (%)

∑ =

1024

(Hyperdistension pixel × Sigh 0 Compliance pixel )

Pixel =1



1024

Sigh 0 Compliance pixel

Pixel =1

5. The heterogeneity of the regional distribution of tidal ventilation dynamically assessed along inspiration (intratidal ventilation heterogeneity: VtHit): we defined VtHit as the average value of the Vtnondep/Vtdep ratios along inspiration when Vt was divided into eight equal-volume parts, as previously described (23, 24). In tables, we will report all the EIT measures as raw impedance results (in a.u.) as well as after transformation into volume by the volume/impedance conversion factor obtained during tidal ventilation. However, since statistical analyses yielded the same results for both measures and to stress the physiological and clinical relevance of our findings, in the Results and Discussion sections we will refer only to volume-transformed data. Statistical Analysis Sample size was chosen to detect an EELVgl increase of 100 ± 150 mL (14, 15) between Sigh0 and Sigh0.5 phases, with power of 0.8 and α of 0.05. Comparisons between two groups of normally distributed variables were performed by independent samples t test, whereas nonnormally distributed variables were compared by Mann-Whitney U test. Differences between variables obtained during each study phase were tested by one-way analysis of variance (ANOVA) for repeated measures or by one-way repeated-measures ANOVA on ranks for nonnormally distributed variables; post hoc comparisons were carried out by Dunnet method, with Sigh0 phase as reference. Association between two variables was assessed by linear regression. Multivariate backward stepwise regression was performed to identify independent predictors of mortality including only variables significantly different at the univariate analysis (i.e., Pao2/Fio2 and VtHit: supplemental data, Supplemental Digital Content 1, http://links.lww.com/ CCM/B308). A p value less than 0.05 (two-tailed) was considered as statistically significant. Normally distributed data are indicated as mean ± sd, whereas median and interquartile range are used to report nonnormally distributed variables. Statistical analyses were performed by SigmaPlot 11.0 (Systat Software, San Jose, CA). Detailed description of the specific methods used to perform this study can be found in the supplemental data (Supplemental Digital Content 1, http://links.lww.com/CCM/B308).

RESULTS Patients’ Characteristics Patients’ main characteristics are reported in Table 1. Patients were 66 ± 12 years old and 10 (50%) were women. On the day of the study, lung injury score scores were in the moderate to severe range for all patients and 15 patients (75%) fulfilled acute respiratory distress syndrome (ARDS) criteria. The etiology of September 2015 • Volume 43 • Number 9

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Clinical Investigations

Table 2. Global and Regional Lung Aeration, Ventilation, and Heterogeneity (Expressed Both

as Raw Impedance Data and After Transformation Into Volume) at Different Sigh Rates Variable

Sigh0

Sigh0.5

Sigh1

EELVgl (mL)

Baseline

156 (88–288)b

EELIgl (a.u.)

Baseline

968 ± 802

EELVnondep (mL)

Baseline

EELInondep (a.u.)

pa

Sigh2

242 (164–333)b

292 (200–396)b

< 0.001

b

1291 ± 777

1546 ± 841

< 0.001

b

134 ± 114

169 ± 126

Baseline

621 ± 564

865 ± 685

EELVdep (mL)

Baseline

58 (7–103)

74 (–4 to 127)

EELIdep (a.u.)

Baseline

347 ± 434

426 ± 473

Vtgl (mL)

475 ± 94

457 ± 108

430 ± 102

Vtgl (a.u.)

2543 ± 1069

2534 ± 1250

2295 ± 1095

2239 ± 1035

Vtnondep (mL)

299 ± 101

286 ± 113

278 ± 119

273 ± 130

0.11

Vtnondep (a.u.)

1607 ± 858

1598 ± 1041

1484 ± 957

1456 ± 1011

0.13

150 ± 69

b

b

217 ± 152

b

b

1050 ± 692

b

b

b

< 0.001

b

< 0.001

b

b

92 (28–137)

< 0.01

b

492 ± 420

b

< 0.001

b

423 ± 113

b

< 0.05

b

b

b

< 0.01

Vtdep (mL)

175 ± 78

171 ± 74

153 ± 64

Vtdep (a.u.)

932 ± 548

935 ± 550

812 ± 469

783 ± 463

Vtnondep (%)

63 ± 15

62 ± 16

63 ± 17

63 ± 18

0.66

Vtdep (%)

37 ± 15

38 ± 16

37 ± 17

37 ± 18

0.65

VtHit

2.0 ± 1.3

1.8 ± 1.3b

2.0 ± 1.5

2.1 ± 1.5

< 0.05

b

< 0.01

b

b

b

< 0.01

EELV = end-expiratory lung volume, EELI = end-expiratory lung impedance, gl = global, a.u. = arbitrary units, nondep = nondependent lung region, dep = dependent lung region, Vt = tidal volume, VtH = heterogeneity, it = intratidal (see text and supplemental data, Supplemental Digital Content 1, http://links.lww.com/CCM/B308). a p value by one-way analysis of variance (ANOVA) for repeated measures or by one-way repeated-measures ANOVA on ranks. b p < 0.05 by post hoc comparisons (Dunnet method) versus Sigh0.

respiratory failure was infectious in 13 patients (65%) and primary in 10 patients (50%). Seven patients (35%) died during their hospital stay (Table 1). During all study phases, pressure support level was 8 ± 2 cm H2O with PEEP 8 ± 2 cm H2O and Fio2 0.5 ± 0.1 (Table 1). As a rough reference, in all but four patients (20%), clinical PEEP level corresponded to the lower PEEP-ARDSnet table (25). For the remaining four patients,

Figure 1. Sigh induces lung recruitment. In acute respiratory failure patients undergoing protective pressure support, addition of short cyclic recruitment maneuver (Sigh) induces significant reaeration (∆EELVgl) of previously collapsed lung (i.e., recruitment) in comparison to baseline pressure support ventilation. *p < 0.05 versus baseline. ANOVA = analysis of variance.

Critical Care Medicine

two had relatively low PEEP because of risk of hemodynamic instability, whereas the other two patients were at risk for alveolar hemorrhage and had higher PEEP. Effects of Sigh on Regional Lung Strain, Ventilation Heterogeneity, and Hyperdistension At all Sigh rates, EELVgl increased (Table 2 and Fig. 1) in comparison to baseline Sigh0 due to recruitment across all lung regions. Indeed, both EELVnondep and EELVdep significantly increased (Table 2 and Figs. 2 and 3), with higher values for nondependent regions (173 ± 133 mL vs 87 ± 115 mL, p < 0.001). Furthermore, at Sigh1 and Sigh2, global Vt decreased (Tables 2 and 3) and, regionally, Vtnondep showed a trend toward reduction and Vtdep was significantly reduced (Table 2). Global and regional Crs values did not change with introduction of Sigh. However, a trend toward improvement seemed evident for Crsdep. Vt%nondep and Vt%dep did not change significantly with introduction of Sigh (Table 2). Nonetheless, along inspiration, VtHit decreased during the Sigh0.5 phase, while it did not vary during the other two (Table 2 and Fig. 4). During all Sigh phases, Crs-Sighnondep did not differ from tidal Crsnondep (data not shown, p > 0.05) and cumulated hyperdistension was decreased in comparison to baseline PSV (Table 3). Physiological Effects of Sigh Table 3 reports the effects of Sigh on gas exchange, ventilation parameters, and hemodynamics. Oxygenation improved at all www.ccmjournal.org

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Mauri et al

multivariate regression analysis (β = –0.511 with se = 0.002, p = 0.01 and β = 0.393 with se = 0.006, p = 0.04, respectively) (Fig. 5).

DISCUSSION Study Main Findings In acute respiratory failure patients undergoing assisted mechanical ventilation, in addition to improving oxygenation, low-, intermediate-, and high-rate Sigh increases regional EELV and decreases regional Vt, thus yielding lower regional lung strain. Furthermore, low-rate Sigh (delivered every other minute) reduces dynamic intratidal regional ventilation heterogeneity. Effects of Sigh on Regional Lung Strain To date, various studies performed in patients receiving protective mechanical ventilation showed quite strong correlation between lung strain and VILI, both at the regional and global level (2, 5, 7, 8). Regional lung recruitment (i.e., reaeration of previously collapsed lung regions) might increase regional EELV and reduce regional lung strain. This Figure 2. Effects of Sigh on regional lung volumes. Airway pressure (Paw) and global and regional lung volume should hold particularly true (LV) tracings from a representative patient enrolled in this study: addition of one Sigh per minute (Sigh1 phase, right end of the tracings) to standard pressure support ventilation (Sigh0 phase, left) induces sudden and stable when regional recruitment is iso-positive end-expiratory pressure increase in end-expiratory lung volume (EELV) across all lung regions, gained without inducing exceswith mean airway pressure changing only by 1–2 cm H2O. Thus, the increase in EELV measured by electrical sive alveolar hyperdistension. impedance tomography should correspond to regional alveolar recruitment. In this study, we showed that low- and high-rate Sigh induces Sigh rates (Table 3) with mean airway pressure significantly diffuse regional lung recruitment without increasing hyperdisincreasing, albeit by only 1–2 cm H2O (Table 3). At increastension. Our finding that Sigh induces alveolar recruitment both ing Sigh rates, mandatory minute ventilation granted by Sigh in dependent and nondependent regions is new but not unex(MVSigh) increased but MVtot didn’t change as patients decreased pected: in fact, it mirrors the heterogeneous distribution of lung RRspont and Vt to maintain stable Pco2 and pH (Table 3). Placollapse described by computerized tomography studies (26). teau pressure decreased during Sigh1 and Sigh2 phases as comFurthermore, Crotti et al (27) already described that recruitment pared with baseline Sigh0 (Table 3) and, consecutively, PMI occurs progressively from nondependent lung regions (where decreased during Sigh1 and Sigh2, while inspiratory muscular the super-imposed pressure to lung structures by edema is lower) activity seemed more preserved during Sigh0.5 (Table 3). to the dependent ones and our finding seems to confirm their results. We also showed that Sigh decreases patients’ inspiratory Variables Associated With Patients’ Outcome effort (i.e., reduced PMI) as a consequence of the additional Pao2/Fio2 and VtHit values measured during baseline PSV mandatory ventilation due to Sigh. Reduced inspiratory effort phase (Sigh0) were independent predictor of mortality at led to decreased regional tidal volumes, and it indirectly helped 1828

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Clinical Investigations

overexpansion of contiguous lung regions) is increasingly recognized as a key factor for ventilation heterogeneity, VILI, and mortality of mechanically ventilated patients (3). Heterogeneity, indeed, is a multiplication factor for the stretching forces imposed on alveoli by mechanical ventilation, and recent studies showed that patients with higher structural lung heterogeneity have more severe ARDS (3) and they are not protected from VILI, even when ventilation is delivered within protective settings (5, 6). Inhomogeneity of lung structure (3) yields heterogeneous distribution of tidal venFigure 3. Regional recruitment induced by Sigh. Sigh-induced recruitment of previously collapsed alveolar units tilation (4) that in this study happens both in dependent and nondependent lung regions. *p < 0.05 versus baseline for ∆EELVnondep. **p < 0.05 versus baseline for ∆EELVdep. ANOVA = analysis of variance, ∆EELVnondep = change in endwas directly assessed by EIT. expiratory lung volume in nondependent lung region measured by electrical impedance tomography (EIT), In particular, we showed that ∆EELVdep = change in end-expiratory lung volume in dependent lung region measured by EIT. Sigh delivered every 2 minutes is able to decrease dynamic further reducing regional lung strain. In summary, we showed intratidal ventilation heterogeneity, and this might represent that Sigh reduces dependent and nondependent lung strain by another way by which Sigh may enhance regional protection. two different complementary mechanisms: decreased inspiratory Lower Sigh rate decreased intratidal ventilation heterogeneity effort decreases strain numerator value (i.e., regional Vt), while likely because of its unique ability to couple regional recruitalveolar recruitment increases strain denominator value (i.e., ment with preserved diaphragm activity (i.e., unmodified PMI regional EELV). Our study generates the hypothesis that Sigh, by values), both of which are able to increase ventilation homoreduction of regional lung strain, may decrease the risk of VILI geneity (18, 24). (5) and limit its clinical sequelae (28). We also described that intratidal ventilation heterogeneity during baseline PSV is an independent predictor of worse Effects of Sigh on Regional Ventilation Heterogeneity outcome. The correlation between intratidal ventilation hetSince the seminal work by Mead et al (29), structural heterogeneity and outcome might be due to the fact that higherogeneity of the lung (i.e., the coexistence of collapse and est transpulmonary pressure is usually reached during active inspiration (rather than at the end of it) (30): thus, intratidal heterogeneity might regionally increase Paw, leading to higher risk of VILI (31, 32). Our data seem to strengthen previous findings (4, 31, 32), suggesting that in ventilated acute respiratory failure patients, the combination of ventilation heterogeneity with elevated transpulmonary pressure might be key determinants of VILI.

Figure 4. Low-rate Sigh decreases intratidal ventilation heterogeneity (VtHit). Only Sigh delivered once every 2 min could decrease intratidal ventilation heterogeneity. *p < 0.05 versus baseline. ANOVA = analysis of variance, VtHit = mean value of the Vtnondep/Vtdep ratios along inspiration when Vt is divided into eight equal-volume parts (see Methods section).

Critical Care Medicine

Effects of Sigh on Regional Lung Hyperdistension Our study showed that Sigh reduces the strain generated by tidal ventilation but Sigh might also generate excessive strain per se, especially when it delivers a substantial fraction of the MV. Furthermore, one of the benefits associated with the use of assisted ventilation in ARDS is the possibility of regional recruitment without hyperdistension of noncollapsed areas and Sigh could offset these benefits. However, we studied Sigh delivered at relatively safe pressure (i.e., 35 cm H2O) and we also showed that 1) during Sigh, compliance of the nondependent region did not worsen in comparison to tidal ventilation, www.ccmjournal.org

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Table 3.

Physiological Changes Associated With Sigh Sigh0

Sigh0.5

Sigh1

Sigh2

pa

Pao2 (mm Hg)

84.7 ± 11.4

95.2 ± 22.3b

99.0 ± 19.6b

108.0 ± 24.7b

< 0.001

Paco2 (mm Hg)

47.9 (41.6–49.5)

46.4 (41.3–50.7)

47.6 (42.3–50.8)

47.2 (38.6–49.8)

0.76

pH

7.41 (7.39–7.43)

7.41 (7.39–7.43)

7.41 (7.39–7.43)

7.42 (7.40–7.44)

0.29

Variable

Patient’s respiratory rate (breaths/min)

19 (15–22)

16 (14–19)

17 (12–19)

Tidal volume (mL/kg)

7.8 ± 1.6

Sigh volume (mL/kg)



21 (19–24)

22 (19–23)

10.4 ± 1.8

11.0 ± 1.8

11.7 ± 1.6

MVtot (L/min)

7.8 ± 2.0

7.9 ± 1.7

MVSigh (L/min)



0.69 (0.52–0.80)

MVSigh/MVtot (%)



8 (7–10)

Pplat (cm H2O)

19 ± 3

19 ± 4

18 ± 3b

2.0 (0.6–5.0)

2.0 (0.0–4.5)

1.0 (0.0–3.0)b

Mean airway pressure (cm H2O)

PMusc index (cm H2O)

7.5 ± 1.7

7 ± 1.5

12 (10–19)

b

b

< 0.01

b

< 0001

23 (19–25)

12.7 ± 1.7

b

< 0.001

b

7.6 ± 1.8 b

b

6.9 ± 1.7

b b

b

< 0.001

b

8.0 ± 1.9

1.41 (0.97–1.61)

b

17 (15–21)

b

0.47

2.78 (1.90–3.28)

b

34 (31–37)

b

17 ± 3b

< 0.001 < 0.001 < 0.001

0.0 (0.0–2.0)b

< 0.001

Crs (mL/cm H2O)

49 ± 16

51 ± 18

51 ± 14

50 ± 16

0.54

Crsnondep (mL/cm H2O)

32 ± 12

33 ± 14

33 ± 14

32 ± 15

0.88

Crsnondep (a.u./cm H2O)

181 ± 79

188 ± 95

196 ± 104

203 ± 101

0.22

13 (10–23)

16 (11–22)

16 (12–20)

Crsdep (mL/cm H2O)

16 (9–25)

0.32

Crsdep (a.u./cm H2O)

93 ± 52

103 ± 51

104 ± 60

124 ± 102

0.09

Cumulated hyperdistension (%)

Baseline

2 ± 16

–10 ± 35

–19 ± 38

0.03

Mean arterial pressure (mm Hg)

83 (73–88)

79 (72–87)

80 (75–87)

81 (75–89)

0.56

10 ± 3

10 ± 4

10 ± 4

10 ± 3

0.94

Heart rate (breaths/min)

90 (76–102)

89 (76–102)

91 (76–105)

89 (77–101)

0.95

SatCVCO2 (%)

73 (70–78)

73 (70–81)

74 (70–81)

74 (68–82)

0.66

Central venous pressure (mm Hg)

b

MVtot = total patient’s minute ventilation, MVSigh = mandatory minute ventilation granted by Sigh, Pplat = end-inspiration plateau pressure, Crs = static respiratory system compliance, Crsnondep and Crsdep = regional static respiratory system compliance in nondependent and dependent lung measured during tidal breathing, a.u. = arbitrary units, SatCVCO2 = central venous saturation. a p value by one-way analysis of variance (ANOVA) for repeated measures or by one-way repeated-measures ANOVA on ranks. b p < 0.05 by post hoc comparisons (Dunnet method) versus Sigh0. Dashes indicate data are not relevant to this phase.

likely indicating minor intra-Sigh hyperdistension (21); and 2) EIT-based measure of cumulative hyperdistension (22) during tidal ventilation was reduced by introduction of Sigh, probably as a consequence of recruitment. The Search for Sigh “Minimum Effective Dose” This is the first study comparing different Sigh rates in an effort to assess its “minimum effective dose.” We must admit that our data are not conclusive: on one hand, we showed that regional Vt and EELV (i.e., regional strain) are more reduced at higher Sigh rates. On the other, Sigh delivered once every 2 minutes was the only rate able to decrease both strain and ventilation heterogeneity. Figure 5. Intratidal heterogeneity (VtHit) is higher in nonsurvivors. Intratidal ventilation heterogeneity (VtHit) measured during baseline pressure support was higher in patients who died during their hospital stay in comparison with survivors.

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Study Limitations This study has few important limitations including incomplete imaging of the lungs and indirect assessment of alveolar recruitment by EIT, relatively short study phases, and potential September 2015 • Volume 43 • Number 9

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Clinical Investigations

risks associated with the high volume delivered during Sigh. Detailed list and full explanation of study limitations can be found in the supplemental data (Supplemental Digital Content 1, http://links.lww.com/CCM/B308).

CONCLUSIONS In acute respiratory failure critically ill patients undergoing PSV, Sigh improves oxygenation and it may decrease regional strain and ventilation heterogeneity, without additional hyperdistension. Results on Sigh minimum effective dose are not conclusive; however, Sigh delivered once every 2 minutes might be regarded as safe and effective choice. Measures in this study were realized on a single slice of lung, and results should be interpreted cautiously. Nonetheless, the role of Sigh in the care of acute respiratory failure and ARDS patients undergoing assisted mechanical ventilation seems to deserve further prospective validation.

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Effects of Sigh on Regional Lung Strain and Ventilation Heterogeneity in Acute Respiratory Failure Patients Undergoing Assisted Mechanical Ventilation.

In acute respiratory failure patients undergoing pressure support ventilation, a short cyclic recruitment maneuver (Sigh) might induce reaeration of c...
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