Sigh in Acute Respiratory Distress Syndrome

PAOLO PELOSI, PAOLO CADRINGHER, NICOLA BOTTINO, MAURO PANIGADA, FABIOLA CARRIERI, ELENA RIVA, ALFREDO LISSONI, and LUCIANO GATTINONI
Istituto di Anestesia e Rianimazione, Universit di Milano and Servizio di Anestesia e Rianimazione, Ospedale Maggiore IRCCS, Milano, Italy

Mechanical ventilation with plateau pressure lower than 35 cm H2O and high positive end-expiratory pressure (PEEP) has been recommended as lung protective strategy. Ten patients with ARDS (five from pulmonary [p] and five from extrapulmonary [exp] origin), underwent 2 h of lung protective strategy, 1 h of lung protective strategy with three consecutive sighs/min at 45 cm H2O plateau pressure, and 1 h of lung protective strategy. Total minute ventilation, PEEP (14.0 2.2 cm H2O), inspiratory oxygen fraction, and mean airway pressure were kept constant. After 1 h of sigh we found that: (1) PaO2 increased (from 92.8 18.6 to 137.6 23.9 mm Hg, p 0.01), venous admixture and PaCO2 decreased (from 38 12 to 28 14%, p 0.01; and from 52.7 19.4 to 49.1 18.4 mm Hg, p 0.05, respectively); (2) end-expiratory lung volume increased (from 1.49 0.58 to 1.91 0.67 L, p 0.01), and was significantly correlated with the oxygenation (r 0.82, p 0.01) and lung elastance (r 0.76, p 0.01) improvement. Sigh was more effective in ARDSexp than in ARDSp. After 1 h of sigh interruption, all the physiologic variables returned to baseline. The derecruitment was correlated with PaCO2 (r 0.86, p 0.01). We conclude that: (1) lung protective strategy alone at the PEEP level used in this study may not provide full lung recruitment and best oxygenation; (2) application of sigh during lung protective strategy may improve recruitment and oxygenation. Pelosi P, Cadringher P, Bottino N, Panigada M, Carrieri F, Riva E, Lissoni A, Gattinoni L. Sigh in acute respiratory distress syndrome. AM J RESPIR CRIT CARE MED 1999;159:872880.

During the last 20 yr, there has been a remarkable evolution in the ventilatory treatment of acute respiratory distress syndrome (ARDS). In the 1970s, high tidal volume (VT) and pressures were the rule, and the only recognized side effect was hypocapnia (1). The most important damaging factor for the lung was considered the high inspiratory oxygen fraction (FIO2), as emphasized by the ECMO trial (2). In the 1980s, negative effects of high pressure/volume ventilation were demonstrated in animal models (3) and the concept of lung rest (4) was progressively accepted. This led to an increasing use of lower VT in the 1990s, to allow a more gentle treatment of the diseased lung. The accepted side effect was the hypercapnia (5), completely reversing the 1970s concepts. Also, positive end-expiratory pressure (PEEP) has been often revisited during the last 20 yr, from the concepts of best PEEP (6), super PEEP (7), and minimal PEEP (8), to the current concepts, for which PEEP should be adequate to keep open the lung (9) and to prevent intratidal collapse and decollapse (1012). As a result of this long-lasting process of physiology-based conceptual evolution, the Consensus Conference of the American College of Chest Physicians (ACCP) recommended the following guidelines to ventilate patients with ARDS (13): (1)

(Received in original form February 19, 1998 and in revised form October 22, 1998) Correspondence and requests for reprints should be addressed to Professor L. Gattinoni, Istituto di Anestesia e Rianimazione, Universit di Milano, via F. Sforza 35, 20122 Milano, Italy. Am J Respir Crit Care Med Vol 159. pp 872880, 1999 Internet address: www.atsjournals.org

adequate PEEP to support oxygenation, without deleterious effects and evaluated by empirical trial; (2) low VT to avoid a plateau pressure higher than 35 cm H2O; (3) FIO2 below 60%. The low VT approach alone has been tested in prospective randomized trials (14, 15) with at least, in part, discouraging results. The lung protective strategy (16) (i.e., PEEP set 2 cm H2O higher than the inflection point of the pressure-volume curve of the respiratory system and low VT) showed a significant improvement in survival compared with the control subjects, who experienced, however, an unexpected high mortality of 70%. Although the pendulum is now towards the low VT, relatively high PEEP and hypercapnia, we have forgotten that more than 30 yr ago it was clearly shown that low VT during anesthesia in normal lungs leads to progressive lung atelectasis with consequent hypoxemia (17). The atelectasis occurring with time, in this case, was not likely due to compression (which is an immediate phenomenon), but rather to a progressive gas reabsorption caused by a regional gas uptake greater than supply. The lung collapse was, in fact, directly related to the degree of hypoventilation and could be prevented by large tidal volumes, even delivered intermittently. Several reports came to the same conclusion, including studies in patients with ARDS (18, 19). Thus, in this study, we tested the following hypotheses: (1) that the current recommended ventilation, i.e., PEEP thought to be sufficient to keep the lung open at end-expiration and inspiratory plateau pressure equal or lower than 35 cm H2O maintain unresolved atelectasis; (2) that sighs should provide sufficient opening pressure to further recruit the lung and should provide sufficient volume to prevent new reabsorption

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rived: (1) Starting compliance (Cstart). This was computed as the ratio between the first 100 ml inflation and the corresponding pressure. (2) Inflation compliance (Cinf). This was computed as the slope of the P-V curve during inflation in its most linear segment. (3) Lower inflection point (LIP). This was computed as the pressure corresponding to the intersection between Cstart and Cinf lines. From these parameters, two possible PEEP levels for clinical use may be identified and defined: (1) Pflex-PEEP as PEEP 2 cm H2O higher than the inflection point; (2) linear-PEEP as PEEP equal to the minimal pressure at which the slope of the P-V curve becomes linear (22). PEEP trial. The PEEP trial was performed with the VT in clinical use (6 to 8 ml/kg), and applying 5, 10, 15, 20 cm H2O PEEP. Inspiratory oxygen fraction and respiratory rate were maintained constant. If at a given PEEP level, the plateau pressure exceeded 35 cm H2O, the VT was reduced until the plateau pressure was equal to 35 cm H2O. This set (applied PEEP and VT with plateau not exceeding 35 cm H2O) was maintained for at least 20 min, after which blood gases were determined. We defined trial-PEEP the PEEP at which the greater PaO2 improvement was observed. The PaO2 was considered arbitrarily not improved, if its increase was equal to or lower than 10 mm Hg. Selection of PEEP. In this study we chose to apply the trialPEEP according to the ACCP Conference recommendations (13). This (see RESULTS) was the highest PEEP selected by the three different methods and was therefore most likely to prevent collapse at endexpiration. Ventilatory setting. After selecting PEEP and VT, the ventilatory setting has been defined and reported in Table 2. No intrinsic PEEP was detected in this series of patients.

atelectasis, which otherwise may develop if too low VT is used, despite a PEEP selected as currently recommended (13); (3) that all the above phenomena should be quantitatively different in ARDS from pulmonary and extrapulmonary origin as they may have, for a given plateau pressure, different transpulmonary pressures because of the differences in chest wall elastance (20).

METHODS
The study was approved by the institutional review board of our hospital, and informed consent was obtained from the patients next of kin.

Study Population
We studied 10 consecutive, unselected patients, who met the ARDS criteria of the American European Consensus Conference on ARDS (21). None of them had asthma, chronic lung diseases, or cardiogenic pulmonary edema. The main demographic and clinical characteristics and the time from onset, as well as outcome, are summarized in Table 1.

Study Design
All the patients were nasotracheally intubated with a cuffed endotracheal tube, ventilated with a Siemens Servo ventilator 300 C (Siemens, Erlanger, Germany) and had an arterial and pulmonary artery thermodilution catheter inserted. During the study, the patients were sedated with fentanyl and diazepam and paralyzed with pancuronium bromide. The entire study lasted 4 h, which were divided in three periods: baseline period (2 h), sigh period (1 h), and no sigh period (1 h). Measurements were taken at the end of the baseline period, at 30 min and 60 min of the sigh period, and at 30 min and 60 min of the no sigh period.

Sigh Period
To provide a sigh function with the Siemens Servo ventilator 300 C, a software program was developed by one of us (P.C.), which determined automatically the volume or the pressure of the sigh, its rate (1, 2, 3, . . . /min), and its sequence (consecutive sighs or separated). We chose to deliver a sequence of three consecutive sighs per minute with the volume such as to reach 45 cm H2O plateau pressure in volume control mode. The number of no-sigh VT was automatically reduced to maintain a minute ventilation (VE) similar to that at baseline. The ventilatory setting during the sigh period is summarized in Table 2. As shown, PEEP, Paw, VE, and FIO2 were identical during the baseline period and the sigh period.

Baseline Period
Our aim during this period was to provide the kind of mechanical ventilation that is recommended in ARDS, i.e., PEEP level thought to be sufficient to keep the lung open, and VT such as to maintain the plateau pressure equal or below 35 cm H2O, accepting possible hypercapnia as a side effect, as recommended by the ACCP Conference (13) and by Amato and colleagues (16). To select PEEP we performed, prior to the baseline period, two maneuvers: a static pressurevolume (P-V) curve of the respiratory system, and a PEEP trial. Pressurevolume curve. The static P-V curve was determined without previous homogenization for lung volume hystory, using an automatic supersyringe, and inflating the lung stepwise up to 1.4 L, starting from atmospheric pressure (100 ml per step, 2-s interval between the steps) (22). From the P-V curve the following parameters were de-

No-Sigh Period
After the sigh period, the baseline ventilation was reinstituted for 1 h, with the same ventilatory setting implemented during the baseline ventilation (Table 2).

TABLE 1 PATIENT CHARACTERISTICS AND OUTCOME*

Patient No. ARDSp 1 2 3 4 5 ARDSexp 6 7 8 9 10 Mean SD Sex (M/F ) M M M M M F M M F M 8M/2F 53.2 Age (yr) 47 26 74 63 51 40 68 58 65 63 12.2 76.7 Weight (kg) 75 69 70 95 85 50 83 80 75 85 Height (m) 1.72 1.70 1.70 1.81 1.75 1.53 1.76 1.72 1.61 1.75 12.2 1.7 0.1 2.9 Days of Intubation 3 5 3 2 3 3 4 2 2 2 1.0 2.3 Days of ARDS 3 2 3 2 3 2 2 2 2 2 0.5 Diagnosis Pneumocystis carinii Pn Pneumocystis carinii Pn Cytomegalovirus Pn Pseudomonas aeruginosa Pn Herpes simplex virus Pn Abdominal sepsis Pancreatitis Abdominal sepsis Osteomielitis Abdominal sepsis Outcome (S/D) D D S D S S D S D S 5S/5D

Definition of abbreviations: ARDSp ARDS from pulmonary disease; ARDSexp ARDS from extrapulmonary disease; Days of ARDS elapsed days from the time in which the ARDS criteria were met and the time of the study; D died; Days of intubation elapsed days from the time of intubation to the time of the study; Pn pneumonia; S survived. * Data are expressed as mean SD.

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TABLE 2 VENTILATORY SETTINGS*
Sigh Period Baseline VTB, L RRB, breaths/min V B, L S 1 TIB, s TI/TtotB PlatB, cm H2O Paw B, cm H2O V EB, L/min VTS, L RRS, breaths min V S, L s 1 TIS, s TI/TtotS PlatS, cm H2O PawS, cm H2O V ES, L min 1
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No-Sigh Period 60 min 0.56 9.8 0.46 1.3 0.32 28.8 19.2 5.5 1.1 3.0 0.46 2.5 0.32 42.2 19.9 3.3 19.3 77 12.8 8.5 14.0 0.11 3.9 0.16 0.3 0.10 3.8 2.0 1.8 0.45 0.0 0.16 1.1 0.07 3.0 2.9 1.4 2.1 16 3.9 2.0 2.0 19.6 77 15.5 8.5 14.0 30 min 0.56 15.5 0.45 1.3 0.33 30.5 19.6 8.7 2.2 16 3.4 2.1 2.0 19.5 77 15.5 8.6 14.0 0.12 3.4 0.16 0.3 0.10 4.6 2.2 2.1 60 min 0.56 15.5 0.45 1.3 0.33 30.7 19.5 8.7 2.1 16 3.4 2.1 2.0 0.12 3.4 0.17 0.3 0.10 4.6 2.1 2.1

1 min 0.56 9.8 0.46 1.3 0.32 31.6 19.6 5.5 1.1 3.0 0.46 2.5 0.32 45.0 20.2 3.3 0.11 3.9 0.16 0.3 0.10 3.7 2.1 1.8 0.45 0.0 0.16 1.1 0.07 1.1 2.7 1.3 2.1 16 3.9 2.0 2.0

30 min 0.56 9.8 0.45 1.3 0.33 29.6 19.2 5.5 1.1 3.0 0.45 2.5 0.33 43.8 20.2 3.3 19.4 77 12.8 8.5 14.0 0.11 3.9 0.16 0.3 0.10 4.6 1.9 1.8 0.45 0.0 0.16 1.1 0.07 3.4 2.7 1.3 1.9 16 3.9 2.0 2.0

0.56 15.5 0.46 1.3 0.32 31.6 19.6 8.5 19.6 77 15.5 8.5 14.0

0.11 3.4 0.16 0.3 0.10 3.6 2.1 2.1

PawP, cm H2O FIO2, % RRtot, breaths min V Etot, L min 1 PEEP, cm H2O

2.1 16 3.4 2.1 2.0

19.7 77 12.8 8.5 14.0

Definition of abbreviations: FIO2 oxygen inspiratory fraction; Index B measurements taken from breaths without sigh; Index S measurements taken from breaths with sigh; Paw mean airway pressure; PawP weighted mean airway pressure between sigh and nosigh breaths in a minute; Plat plateau pressure; PEEP positive end-expiratory pressure; RR respiratory rate; RRtot RRS RRB; TI inpsiratory time; TI/Ttot inspiratory time to total respiratory time ratio; V inspiratory flow; V E expired minute ventilation; VEtot VEB VES; VT tidal volume. * Data are expressed as mean SD. p 0.05; p 0.01, compared with baseline period; p 0.01, compared with 1 min of sigh period.

Gas-Exchange and Hemodynamics

Gas tensions and pH were analyzed immediately after sampling from . . arterial and mixed venous blood. The venous admixture (QVA/Q) was computed by the shunt equation, assuming a respiratory quotient equal to 1. Mean arterial (Pa ), pulmonary artery (Ppa ), pulmonary wedge (Ppw ), and central venous (PCV ) pressures were measured with pressure transducers zeroed at the midaxillary line. Cardiac output (CO) was measured in triplicate by the thermodilution method, and the cardiac index (CI) was computed normalizing the CO for the body surface area. The oxygen consumption (VO2) was computed using the reverse Fick equation, and the dead space fraction (VD/VT) was estimated rearranging the Bohr equation and assuming a respiratory quotient 1, according to the following formula (23): V D V T = 1 [ V O 2 ( P B 47 ) ] ( Pa CO2 V E ) in which PB is the atmospheric pressure. This formula implies that oxygen consumption equals the metabolic CO2 production, and the lat ter equals the CO2 excreted. The assumption that VCO2 equals VCO2 excreted holds true if the system is at steady state; the equilibration, when changing the alveolar ventilation, takes 20 to 30 min (24), and our samples were taken after 1 h of sighing, with the system at new steady state. The effective ventilation/perfusion ratio was defined as: VA/COeff . . (VE VD)/CO (1 QVA/Q), in which VA is the alveolar ventilation and COeff is the cardiac output effectively perfusing the ventithe shunt flow). The VA/COeff reflects the lated regions (i.e., CO average ventilation to perfusion ratio occurring in the ventilated/perfused pulmonary units.

EELV measured at the end of the sigh period, and we defined derecruitment ( EELV) as the differences between the EELV measured at the end of the sigh period and the EELV measured 1 h after the sigh interruption. It is important to emphasize that the conditions of the EELV measurement were identical (at end-expiration with identical PEEP). Thus the differences in EELV represent the lung volume gained or lost because of the different operating conditions (sighing and no sighing).

Respiratory Mechanics
Details have been previously published and will only be summarized here (20). Airway pressure (Pao) was measured proximal to the endotracheal tube, and the esophageal pressure (Pes) was measured with an esophageal balloon inflated with 0.5 to 1 ml of air. Gas flow was recorded with a heated pneumotachograph connected to a differential pressure transducer. Volume was obtained by digital integration of the flow signal. Both flow and pressure signals were recorded on a personal computer and processed via an analog-to-digital converter (Colligo, Elekton, Italy) at a sample rate of 200 Hz and were stored on diskettes for subsequent computer analysis. Static elastance of total respiratory system, lung, and chest wall. Static elastance of the total respiratory system (Est,rs) was computed as Est,rs Pao/VT, where Pao is the difference between endinspiratory and end-expiratory airway pressure. Static elastance of the chest wall (Est,w) was computed as Pes/VT, where Pes is the difference between end-inspiratory and end-expiratory esophageal pressure. Static lung elastance (Est,L) was calculated as Est,L Est,rs Est,w. Resistance of the total respiratory system, lung, and chest wall. Maximum (Rmax,rs) and minimum (Rmin,rs) resistance of the respiratory system were computed from Pao as (Pmax P2)/ V and (Pmax P1)/ V, where Pmax is the maximal pressure value after occlusion, P1 is the pressure recorded after the immediate drop from Pmax, P2 is the pla teau pressure, and V is the flow immediate preceding the occlusion. Rmin,rs represents the ohmic resistive component of the respiratory system, and Rmax,rs includes Rmin,rs plus the additional respiratory resistance (DR,rs). Because there was no appreciable drop in Pes

End-Expiratory Lung Volume and Lung Recruitment

The end-expiratory lung volume (EELV) was measured using a simplified closed-circuit helium dilution method (20) during an endexpiratory pause, maintaining the PEEP in use and inflating 1 to 1.5 L into the respiratory system 10 to 15 times. We defined recruitment ( EELV) as the differences between baseline EELV and the

Pelosi, Cadringher, Bottino, et al.: Sigh in ARDS

TABLE 3 PEEP SELECTION
PEEP PaO2/PaCO2 (mm Hg) 5 cm H2O 87/36 60/42 55/37 55/52 80/38 45/100 51/44 78/45 53/63 62/50 62.6/51.0 14.1/19.0 10 cm H2O 102/40 76/41 72/38 60/53 93/37 61/98 96/43 116/47 67/66 88/46 83.1/51.2 18.8/18.6 PaO2/PaCO2 (mm Hg) 15 cm H2O 121/42 71/48 89/38 84/53 110/46 82/97 94/42 97/46 80/65 100/47 92.8/52.6 14.9/17.3 20 cm H2O 110/47 62/59 95/51 91/64 86/55 67/115 72/50 103/44 75/67 107/51 86.8/60.6 17.2/20.7

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Patient No. ARDSp 1 2 3 4 5 ARDSexp 6 7 8 9 10 Mean SD

FIO2 (%) 100 70 70 100 60 100 60 70 70 70 77 16

Trial-PEEP (cm H2O) 15 10 15.3 14.2 15 15 12 11.8 16.4 15.4 14.0 2.2

Linear-PEEP (cm H2O) 12 10 10.5 3.9 8.3 2.3 6.5 7.7 5 5 7.1 3.1

Pflex-PEEP (cm H2O) 13.5 10.1 12.5 5 9.2 3.8 6.5 7.5 7 7 8.2 3.2

Definition of abbreviations: ARDSp ARDS from pulmonary disease; ARDSexp ARDS from extrapulmonary disease; FIO2 inspiratory fraction of oxygen; PEEP positive end-expiratory pressure; Trial-PEEP values pressures measured directly during the trial. Thus, they are sometimes slightly different from the values set at the beginning of the trial with the knob of the ventilator.

immediately after the occlusion, Rmin,rs reflects essentially the airway resistance (Rmin,L) and minimum chest wall resistance (Rmin,w) can be considered negligible. As a consequence, maximum chest wall resistance (Rmax,w) is entirely due to the viscoelastic properties of the chest wall tissues (i.e., Rmax,w DR,w). Additional resistance of the lung (DR,L) was obtained as DR,rs DR,w, whereas the sum DR,L gives the maximum lung resistance (Rmax,L). of Rmin,L Rmax,rs, Rmax,L, and Rmin,L include the endotracheal tube resistance.

Statistical Methods
All data are expressed as mean standard deviation. Comparisons between different periods were performed using the analysis of variance. Individual comparisons with baseline were performed using the paired t test; Bonferronis correction was applied for multiple comparisons. To compare pulmonary and extrapulmonary ARDS, Wilcoxons test for unpaired data was applied. The least-squares method was used to perform linear regression analysis (25); a p value lower than 0.05 was considered statistically significant.

constant throughout the study (Table 2). Despite that, the introduction of three sighs at 45 cm H2O plateau pressure led to a significant improvement of PaO2 (average increase at 60 min, 44.8 16.0 mm Hg [50.1 21.7%], range from 16 to 65 mm Hg), together with a significant reduction in QVA/Q (average decrease at 60 min, 10 10% [ 26.4 26.4%], range from 0.1 to 29%) and PaCO2 (average decrease at 60 min, 3.6 4.4 mm Hg [ 6.6 8.5%], range from 2.2 to 11.3 mm Hg). During the study, pHa did not change significantly, being 7.34 0.05 at baseline, 7.34 0.06 at 60 min after application of sigh, and 7.33 0.06 at 60 min after interruption of sigh. However, as shown in Figure 1, all the gas exchange variables returned to the baseline values by 30 min after sigh interruption, and they remained stable until the end of the study. It is worth not-

RESULTS
PEEP Selection

The results obtained with the PEEP trial and the values of linear-PEEP and Pflex-PEEP derived from the P-V curve of each individual patient are reported in Table 3. The PEEP trial, performed as described in METHODS, allowed us to select a PEEP ranging between 10 and 15 cm H2O. Interestingly, we did not find any correlation between the PEEP values derived from the P-V curve, i.e., Pflex-PEEP and linear-PEEP and the trial-PEEP (r 0.007 and r 0.25, respectively). As shown in Table 3, the PaO2 at 20 cm H2O of PEEP was not significantly different from the PaO2 at 15 cm H2O of PEEP. More interestingly, the PEEP selected with the trial-PEEP led to an average PaO2 of 95.5 15.9 mm Hg, which was significantly (p 0.05) higher than the PaO2 recorded at 20 cm H2O of PEEP (86.8 17.7 mm Hg).
Gas Exchange

The behavior of the most important gas exchange variables is shown in Figure 1. It is important to remember that PEEP, FIO2, mean airway pressure, and minute ventilation were kept

Figure 1. Data are presented as mean SD. PaO2 (open bars) and PaCO2 (stippled bars) at the end of baseline period, at 30 min, and at 60 min of the sigh period, and at 30 min and 60 min of the nosigh period. In the upper panel is shown the time course of the venous admixture (QVA/Q). *p 0.05, **p 0.01, compared to the baseline period.

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ing, however, that the increase in PaO2 and the decrease in PaCO2 and shunt during sighing were not significantly correlated with the opposite change during the no-sigh period (r 0.56, r 0.32, r 0.38, respectively), i.e., the patients in whom gas exchange improved were not the same as those whose gas exchange deteriorated after sigh interruption.
Respiratory Mechanics

served elevated CI, PVR, and Ppa and decreased systemic vascular resistances. The introduction of three sighs per minute led to a small but significant decrease of Ppa and PVR (average decrease at 60 min, 2.5 1.9 mm Hg [ 8.5 6.9%], range from 6 to 0 mm Hg and 30.8 27.8 dyne s cm 5 m 2 [ 16.4 15.6 %], range from 84.1 to 2.9 dyne s cm 5 m 2, respectively), which returned to the baseline values after the sigh interruption.
Lung Recruitment and Derecruitment, Gas Exchange, Respiratory Mechanics, and Hemodynamics

The behavior of the most relevant mechanical variables is reported in Figure 2. As shown, during the baseline period, the 16.9 and Est,rs and Est,L were abnormally elevated (34.3 27.0 16.7 cm H2O L 1, respectively), whereas Est,w was only slightly increased compared with normal (7.3 3.9 cm H2O L 1). The EELV at PEEP was 1.49 0.58 L. Sighing led to a consistent and significant reduction in 6.6 cm Est,rs and Est,L (average decrease at 60 min, 6.0 9.1%], range from 1.92 to 24.23 cm H2O L 1 [ 16.3 7.1 cm H2O L 1 [ 23.4 13.9%], H2O L 1 and 6.1 from 2.1 to 25.8 cm H2O L 1, respectively), whereas Est,w did not change significantly. After interruption of sighing, in the individual patient, all the mechanical variables returned to baseline values. As well as for gas-exchange, the increase in EELV during sigh period was not significantly correlated (r 0.46) with its decrease during the no-sigh period. The behavior of the resistances of the total respiratory system, lung, and chest wall is summarized in Table 4. During the sigh period Rmax,rs significantly decreased compared with baseline, mainly because of a reduction in Rmax,L. The reduction in Rmax,L was attributable to a reduction in Rmin,L and DR,L. After interruption of sighing all the resistances returned to baseline values.
Hemodynamics

The behavior of the most important hemodynamic variables is reported in Table 5. As shown, during baseline period we ob-

Lung volume recruited during the sigh period averaged 0.423 0.370 L (58.8 16.6%), range from 0.043 to 1.111 L, and the lung volume derecruitment after sigh interruption averaged 0.305 0.243 L ( 19.3 22.7%), range from 0.900 to 0.029 L (Figure 3). Recruitment was associated with a significant increase in PaO2, whereas derecruitment was associated with a decrease in PaO2 (Figure 3). Similar relationships with recruit0.72, ment and derecruitment were observed for PaCO2 (r p 0.01), and QVA/Q (r 0.70, p 0.01). Also, alterations of elastances of both the total respiratory system (r 0.76, p 0.01) and of the lung (r 0.76, p 0.01) were correlated with recruitment and derecruitment. Interestingly the DR,rs, which reflects the viscoelastic properties of the respiratory system, decreased with recruitment and increased with derecruitment (r 0.69, p 0.01) as well as the Rmin,L (r 0.66, p 0.01). In conclusion, both gas exchange and mechanical changes induced by sighing appeared recruitment-dependent. As shown in Figure 4, the derecruitment is a function of PaCO2 and the effective VA/Qeff, i.e., more severe the hypoventilation and lower the effective VA/Qeff ratio greater the derecruitment. PaCO2 and effective VA/Qeff were also correlated (r 0.84, p 0.01) and it is interesting to note (Figure 4) that when VA/Qeff is close to 1, and the PaCO2 is close to 40 mm Hg, the derecruitment is close to zero.
ARDS from Pulmonary and Extrapulmonary Disease

As shown in Table 1, in this series of 10 consecutive patients with ARDS, five had pulmonary and five extrapulmonary ARDS. Despite the limited number of patients, the quantitative differences in most of the variables considered above appear to be relevant. In particular, as previously observed, the Est,w was significantly higher in ARDSexp than in ARDSp (10.6 2 cm H2O L 1 and 4.0 1.3 cm H2O L 1, respectively, p 0.01). The potential for recruitment with sigh appeared different between ARDSp and ARDSexp, being 0.160 0.132 L and 0.688 0.343 L, respectively, p 0.01. Conse quently, during the sigh period, the PaO2 increase and the QVA/Q decrease were significantly different between the two populations (Figure 5).

DISCUSSION
The main findings of this study were that: (1) setting the ventilatory treatment according to the current recommendations does not exploit the full potential for lung recruitment and oxygenation; (2) introducing 45 cm H2O pressure-limited sighs leads to further recruitment and improvement in oxygenation; (3) if we consider our three sequential sighs similar to a recruitment maneuver, it is evident that opening the lung for a limited period is not enough to prevent, with time, the loss of gas volume and gas-exchange deterioration, possibly because of reformation of atelectasis at PEEP levels used in this study; (4) the above effects are quantitatively different in pulmonary and extrapulmonary ARDS.

Figure 2. Data are presented as mean SD. Static elastance of the total respiratory system (Est,rs) (stippled bars), of the lung (Est, L) (open bars), and of the chest wall (Est,w) (hatched bars), at the end of the baseline period, at 30 min, and at 60 min of the sigh period, and at 30 min and 60 min of the no-sigh period. In the upper panel is shown the end-expiratory lung volume (EELV) measured at the end of baseline period and at the end of the sigh period (60 min) and at the end of the no-sigh period (60 min). *p 0.05, **p 0.01, compared with baseline period.

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TABLE 4 RESISTANCE OF THE TOTAL RESPIRATORY SYSTEM, LUNG, AND CHEST WALL*
Sigh Period Baseline s Rmax,rs, cm H2O L Rmax,L, cm H2O L 1 s Rmax,w, cm H2O L 1 s Rmin,rs, cm H2O L 1 s DR,rs, cm H2O L 1 s DR,L, cm H2O L 1 s Sigh breath Rmax,rs, cm H2O L 1 s Rmax,L, cm H2O L 1 s Rmax,w, cm H2O L 1 s Rmin,rs, cm H2O L 1 s DR,rs, cm H2O L 1 s DR,L, cm H2O L 1 s
1

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No-Sigh Period 60 min 30 min

30 min 20.9 18.9 1.9 16.6 4.2 2.3 20.8 18.7 2.0 12.7 8.0 6.0 11.8 11.1 1.0 10.7 3.4 3.0 11.2 10.9 1.2 8.7 6.6 6.5

60 min 28.5 26.5 2.0 20.4 8.2 6.1

respiratory sys-

28.3 26.3 1.9 20.2 8.0 6.1

14.5 13.9 1.0 12.3 4.2 3.8

19.9 18.0 1.9 15.6 4.3 2.4 20.3 18.4 1.9 12.6 7.7 5.8

11.3 10.9 0.7 10.3 3.3 3.0 11.2 10.7 1.2 8.8 6.5 6.3

26.2 24.2 2.0 19.2 6.7 5.0

13.7 13.1 0.9 12.4 4.4 4.4

14.3 13.4 2.2 12.0 4.2 3.7

Definition of abbreviations: DR viscoelastic resistance; L lung; Rmax tem; w chest wall. * Data are expressed as mean SD. p 0.05; p 0.01, compared with baseline values; p 0.05; p

total resistance; Rmin

ohmic resistance; rs

0.01, compared with no-sigh period.

PEEP Selection

Current recommendations suggest to select a PEEP level adequate for oxygenation, avoiding excessive stretching, hemodynamic impairment (13), and prevention of intratidal collapse and decollapse (12). However, the method to select this ideal PEEP, if it exists, is still being debated. As shown in Table 2, some of the methods used to select PEEP gave different results. The PEEP levels derived from the P-V curve (the linear-PEEP and Pflex-PEEP), although in line with several previous reports (22, 26, 27), were significantly lower than the trial-PEEP and unrelated with the latter. As our goal was to apply the PEEP that most likely would prevent the end-expiratory collapse, we used as criterion for PEEP selection the best oxygenation. In fact, in the presence of intratidal collapse and decollapse, the oxygenation should be lower compared with an open lung at end-expiration. The PEEP selected according to oxygenation averaged 14 2 cm H2O, and a further increase to 20 cm H2O did not further improve the oxygenation but, instead, deteriorated it. This indicates that at our selected PEEP, the lung was likely open throughout the respiratory cycle. Furthermore, we previously

found, at the CT scan, that at 15 cm H2O of PEEP the intratidal collapse and decollapse is likely avoided in the majority of patients with ARDS (11). The PEEP values used in the present study were similar, although slightly lower, to the PEEP used in the study of Amato and colleagues (16) with the lung protective strategy (i.e., 16.2 cm H2O). We then thought that, in our study conditions, the selected PEEP could be adequate to likely prevent the end-expiratory collapse (or, at least most of it) and provide a satisfactory oxygenation.
Baseline Period

Our goal was to select a ventilatory setting satisfying the current recommendations, which are based on the gentle treatment of the lung (13) and on prevention of intratidal collapse and decollapse. As previously discussed, we applied a PEEP that was thought adequate to guarantee the respiratory cycle in a relatively open lung, and we limited the plateau pressure to avoid excessive alveolar stretching. The resulting VT (7.3 1.2 ml/kg) and PaCO2 (52.7 19.4 mm Hg) were similar to those reported in several current trials testing low VT in ARDS (14, 15), whereas the PEEP we used was higher, and

TABLE 5 HEMODYNAMICS*
Sigh Period Baseline HR, beats min 1 Pa, mm Hg Ppa, mm Hg PCV, mm Hg Ppw, mm Hg CI, L min 1 m 2 PVRI, dyne s cm 5 m SVRI, dyne s cm 5 m V O2, ml min 1 m 2 DO2, ml min 1 m 2 SvO2, % 118.3 78.1 30.2 11.0 12.6 4.2 102.6 392 118.1 549 74.1 19.3 6.2 5.8 3.1 2.8 1.0 52.4 152 29.4 123 5.8 30 min 119.7 82.7 28.4 11.3 12.7 4.1 94.4 430 132.5 549 74.7 17.6 12.8 6.0 3.0 2.9 0.8 51.1 184 23.1 106 6.0 60 min 118.6 81.4 27.7 11.5 12.9 4.2 86.4 412 124.5 538 75.3 19.0 9.4 6.1 3.0 2.8 0.9 51.3 167 44.4 82 5.5 No-Sigh Period 30 min 119.2 81.8 29.9 11.6 12.9 4.4 93.1 390 116.0 578 75.4 18.8 8.7 6.6 2.7 2.2 1.0 53.7 152 51.3 128 5.9 60 min 117.9 82.5 30.0 11.9 13.1 4.4 94.4 400 124.5 570 74.9 20.3 12.6 6.4 2.4 3.4 1.0 48.8 169 44.0 128 5.5

2 2

Definition of abbreviations: CI cardiac index; DO2 oxygen transport; HR heart rate; Pa mean arterial pressure; PCV central venous pressure; Ppa pulmonary arterial pressure; Ppw pulmonary wedge pressure; PVRI pulmonary vascular resistance index; SvO2 mixed venous hemoglobin saturation; SVRI systemic vascular resistance index; V O2 O2 consumption. * Data are expressed as means SD. p 0.05; p 0.01, compared with baseline period.

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Figure 3. Changes of PaO2 ( PaO2) as a function of changes of endexpiratory lung volume ( EELV). The positive changes of EELV indicate recruitment, the negative changes indicate derecruitment. The relationship is described by the following equation: PaO2 ( 2.4 6.2) (80.0 13.0) EELV, (r 0.82, p 0.01).

the overall mode of our baseline ventilation was very similar to that used in the lung protective strategy of the study of Amato and colleagues (16).
Sigh Period, the Recruitment

Introducing three sighs per minute at 45 cm H2O plateau pressure led to a further lung recruitment, indicating that some pulmonary units had opening pressure greater than 35 cm H2O. We can neither define from our data the pressure required for full lung opening nor can we define the spectrum of opening pressures existing in the ARDS lung. It is possible, however, that the nature of atelectasis and its opening pressure are somewhat related, although only inferences may be made with the available data. We believe that two kinds of atelectasis possibly coexist in ARDS lung: the compression atelectasis and the reabsorption atelectasis. The compression atelectasis develops immediately, as shown by CT scan, because of the increased lung weight, and its anatomic basis is likely the collapse of the small airways at end-expiration (11). As some gas is left behind the collapsed airways, the transmural pressure required for opening is relatively low (12 to 20 cm H2O) (28), i.e., loose atelectasis. The reabsorption atelectasis develops with time, when the regional gas uptake exceeds the delivery, depending on the FIO2, the regional VA/Q, and likely the end-expiratory volume of the pulmonary units. As no gas is left in the pulmonary units, the transmural pressure required for opening may be as high as 30 to 35 cm H2O (28), which may correspond to a plateau pressure as great as 70 cm H2O, i.e., sticky atelectasis. From the observed data, several interpretations may be advanced. It is possible that at end-expiration, with the PEEP levels we used, we still had small airway collapse. In this case, sigh would lead to two effects: (1) recruitment of some sticky atelectasis; (2) greater inflation, with stabilization of the pulmonary units previously collapsing and decollapsing, and consequent improvement of their VA/Q ratios. Alternatively, it is possible that at 14 cm H2O of PEEP, the small airway collapse was prevented, as suggested by the PEEP trial. In this case the effect of sigh was just to recruit part of the sticky reabsorption atelectasis. In both cases it is clear that 35 cm H2O of plateau pressure was not sufficient to fully recruit the lung. The issue of full opening has been mainly emphasized by

Figure 4. Derecruitment after sigh interruption ( EELV) as a function of alveolar ventilation to effective cardiac output ratio (V A/ COeff) (upper panel), and of PaCO2 (lower panel). The relationships are described by the following equations: EELV (L) (0.910 0.163) ( 0.873 0.225) VA/COeff, r 0.81, p 0.01; EELV (L) ( 0.251 0.127) (0.011 0.002) PaCO2 (mm Hg), r 0.86, p 0.01.

Bohn and Lachmann (29) who suggested a recruitment maneuver with pressures largely exceeding 35 cm H2O plateau for short period of time to resolve the sticky atelectasis problem. Lower pressures were thought to be enough thereafter to maintain the lung open if adequate PEEP was provided.
No Sigh Period, the Derecruitment

Unfortunately, interrupting the sigh and resuming the recommended baseline ventilation led to a progressive derecruitment. We have then to explain why part of the pulmonary units that remained open at end-expiration at 14 cm H2O of PEEP during the sigh period did collapse at the same PEEP when the sigh was abolished. Moreover, we have to explain why the patients who most recruited and improved PaO2, shunt, and PaCO2 during the sigh period were not the same patients who most derecruited and deteriorated gas-exchange after sigh withdrawal. These findings suggest, in fact, that the possible mechanisms underlying recruitment and derecruitment are not the same. The derecruitment may occur through two basic mechanisms, one implying mechanical forces and one implying gas reabsorption. In our conditions, it is possible that abolishing the sigh, the unstable pulmonary units with more severe surfactant alterations (maybe the ones opened by sighs) undergo collapse. However, if recruitment and derecruitment would be

Pelosi, Cadringher, Bottino, et al.: Sigh in ARDS

879

Figure 5. Data are presented as mean SD. Differences in recruitment ( EELV), in PaO2 ( PaO2), and in venous admixture ( QVA/Q) induced by sigh at 60 min in ARDS from pulmonary (ARDSp) and extrapulmonary (ARDSexp) origin. *p 0.05, **p 0.01, compared with ARDSp.

only the function of mechanical forces, we would expect that the patients who recruited more, were the same as those who derecruited more. This was not the case in our study. According to our data, one possible reason for derecruitment was the formation of reabsorption atelectasis caused by low VA/Q ratios. In fact, we found that derecruitment was greater with lower VA/Q and greater PaCO2. In these patients with severe ARDS, high FIO2 used and low tidal volume may favor reabsorption atelectasis, which may be prevented by cyclic high tidal volumes (sigh) (30, 31). A similar relationship was found by Bendixen and colleagues (17) during general anesthesia and more recently, formation of reabsorption atelectasis was noted by CT scan after recruitment maneuvers in normal anesthetized subjects (32). In conclusion, although we lack a direct evidence, it is possible that recruitment is mainly a function of the inspiratory plateau pressure, and the derecruitment is mainly a function of VA/Qeff ratio and lack of adequate PEEP levels.
ARDS from Pulmonary and Extrapulmonary Origin

pulmonary or extrapulmonary, and Est,w should be taken into account when recruitment maneuver and sigh are set.
Clinical Consequences

Recruitment appears to be different in ARDSp and ARDSexp (20). In fact, in ARDSp the amount of atelectasis is scarce, as the predominant damage is the consolidation of alveolar units. For a given applied plateau pressure during the sigh (for example, 45 cm H2O), the average change of transpulmonary pressure, i.e., the difference between the plateau pressure and PEEP minus the difference between esophageal pressure at end-inspiration and end-expiration, is relatively high (24.0 5.7 cm H2O) because of the normal Est,w (4.0 1.2 cm H2O L 1). Thus, ARDSp is characterized by low potential for recruitment, which is fully exploited by the high transpulmonary pressure (33). On the contrary, in ARDSexp the amount of atelectasis is much greater. For a given applied plateau pressure during the sigh (for example, 45 cm H2O), the change in transpulmonary pressure is rather low (16.8 4.6 cm H2O) because of the high Est,w (10.7 2.0 cm H2O L 1). Thus, ARDSexp is characterized by a high potential for recruitment, which, to be exploited, needs applied plateau pressures higher then in ARDSp. We have also to consider that our estimate of transpulmonary pressure does not take into account the possible regional variation, i.e., higher in nondependent and lower in the dependent lung regions. Indeed, it is possible that in our study we did not fully exploit the potential for recruitment in ARDSexp since we applied, in both groups, the same plateau pressure to the respiratory system for recruitment. More generally, the ARDS origin,

This study has two limitations, which prevent its immediate translation in clinical practice: (1) the small number of patients; (2) the short observation period. We believe that the first point is of minor importance. Our purpose, in fact, was to investigate physiologic mechanisms and not to study outcomes. What has been clearly shown in this study is that using the recommended guidelines to ventilate patients with ARDS (i.e., relatively high PEEP selected according to the currently accepted methods and limited VT) leads to a persistence of unresolved atelectasis before and after the sigh. The most relevant clinical question is whether the presence of unresolved atelectasis (i.e., keeping the lung not fully open), is detrimental to the lung over a long-term period. We are not aware of any study that has specifically addressed this issue. However, there is some general consensus that the presence of atelectasis may increase the likelihood of infections and induce lung damage. It is believed that at the interface between open and atelectatic lung damaging shear forces are generated, with consequent lung damage, although this concept has more theoretical (34) than experimental evidence. Indeed, if one believes that unresolved atelectasis is dangerous, the lung should be opened and kept open. Although opening may be accomplished in several ways, including the sigh, it is important to emphasize, as shown in this study, that the usual recommended ventilation may not be adequate to maintain the lung open. In this study, we did not test the different possible systems to maintain the recruitment. It is possible that after the sighinduced recruitment, a PEEP increase would be effective to maintain open the recruited lung regions. The cost, however, would be an increase in mean airway pressure, and, if the plateau pressure is maintained equal to or below 35 cm H2O, a tidal volume reduction and further increase of PaCO2, as suggested by the findings of our PEEP trial (see Table 2). It is also possible that if tidal volume is excessively reduced, reabsorption atelectasis may develop with time, despite higher PEEP. Another possibility would be to maintain recruitment with ventilatory techniques designed to improve alveolar ventilation, such as high frequency oscillation, which has been shown to be effective in maintaining recruitment in animal models (35). It is possible that high frequency oscillation can maintain recruitment for hours not because of good overall VA/Qeff ra-

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tios but just because it keeps the end-expiratory pressures at very high levels. Finally, a continuous sigh at pressure, volume, and rate to be defined, may be another alternative to maintain recruitment and prevent reabsorption atelectasis. However, it remains to be determined which would be the most convenient approach, as their relative iatrogeneity has not been established yet.
Acknowledgment : The writers thank the physicians and nursing staff of the Vecla Intensive Care Unit of the Policlinico Hospital for their valuable cooperation and Prof. L Goodman for his helpful suggestions in revising the manuscript. They also thank Siemens for their precious support.

17.

18.

19.

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