Abstract
To assess the possible differences in respiratory mechanics between the acute respiratory distress syndrome (ARDS) originating from pulmonary disease (ARDSp) and that originating from extrapulmonary disease (ARDSexp) we measured the total respiratory system (Est,rs), chest wall (Est,w) and lung (Est,L) elastance, the intra-abdominal pressure (IAP), and the end-expiratory lung volume (EELV) at 0, 5, 10, and 15 cm H2O positive end-expiratory pressure (PEEP) in 12 patients with ARDSp and nine with ARDSexp. At zero end-expiratory pressure (ZEEP), Est,rs and EELV were similar in both groups of patients. The Est,L, however, was markedly higher in the ARDSp group than in the ARDSexp group (20.2 ± 5.4 versus 13.8 ± 5.0 cm H2O/L, p < 0.05), whereas Est,w was abnormally increased in the ARDSexp group (12.1 ± 3.8 versus 5.2 ± 1.9 cm H2O/L, p < 0.05). The IAP was higher in ARDSexp than in ARDSp (22.2 ± 6.0 versus 8.5 ± 2.9 cm H2O, p < 0.01), and it significantly correlated with Est,w (p < 0.01). Increasing PEEP to 15 cm H2O caused an increase of Est,rs in ARDSp (from 25.4 ± 6.2 to 31.2 ± 11.3 cm H2O/L, p < 0.01) and a decrease in ARDSexp (from 25.9 ± 5.4 to 21.4 ± 55.5 cm H2O/L, p < 0.01). The estimated recruitment at 15 cm H2O PEEP was − 0.031 ± 0.092 versus 0.293 ± 0.241 L in ARDSp and ARDSexp, respectively (p < 0.01). The different respiratory mechanics and response to PEEP observed are consistent with a prevalence of consolidation in ARDSp as opposed to prevalent edema and alveolar collapse in ARDSexp.
The acute respiratory distress syndrome (ARDS) is thought to be a uniform expression of a diffuse and overwhelming inflammatory reaction of the pulmonary parenchyma to a variety of serious underlying diseases. The most frequent causes include sepsis, severe pneumonia, peritonitis, and multiple trauma (1, 2).
However, the possible differences in lung dysfunction between ARDS resulting from pulmonary disease and that resulting from extrapulmonary disease have not been examined systematically. Mechanical properties of the respiratory system may be related to underlying pathology, at least in the early phases of ARDS (3). For instance, when the prevalent pathology is lung tissue consolidation such as in pneumonia, application of positive end-expiratory pressure (PEEP) should induce only a moderate lung recruitment, increased elastance of the respiratory system (i.e., reduction of respiratory compliance), and possible alveolar overdistension. On the other hand, when the prevalent pathology is interstitial edema and alveolar collapse, PEEP should induce remarkable lung recruitment, with a decrease of the elastance of the respiratory system (i.e., increase in respiratory compliance).
We hypothesized that ARDS caused by pulmonary disease is associated with predominant consolidation, whereas ARDS caused by extrapulmonary disease is associated with prevalent interstitial edema and alveolar collapse. To test this hypothesis, we studied patients with ARDS of different origins and divided them into two groups. The first group included patients with ARDS caused by a “direct” insult to the lung, i.e., pulmonary ARDS (ARDSp), and the second group included patients with ARDS developing after an “indirect” insult, i.e., extrapulmonary ARDS (ARDSexp). We report here the respiratory mechanics observed in the two types of the syndrome and discuss possible physiopathologic and clinical implications.
Approval for this investigation was granted by the Ethical Committee of our Institution, and informed consent was obtained from the next of kin of the patients before inclusion in the study. Between December 1994 and June 1996, 21 unselected consecutive mechanically ventilated patients with ARDS were examined. Nineteen of them were in-hospital patients and two were patients transferred from other hospitals. ARDS was defined according to the criteria established by the American-European Consensus Conference on ARDS (4), i.e., acute onset, PaO2 /Fi O2 < 200 mm Hg (regardless of PEEP level), bilateral infiltrates seen on frontal chest radiograph, and pulmonary artery occlusion pressure below 18 mm Hg. We excluded patients in whom air leaks prevented a correct measurement of respiratory mechanics.
These 21 patients made up the total population and their data were compared for similarities to and differences from previous studies on ARDS. Twelve patients were assigned to the ARDSp group, and nine were assigned to the ARDSexp group by three independent physicians, blinded as to the results of the measurements, and the clinical course. Assignment was based on history, clinical presentation, and microbiological results (Table 1). As shown in the table all of the patients were studied during the early phase of ARDS. Eleven of the 12 patients with ARDSp had diffuse pneumonia with positive airway cultures, and none had positive blood cultures. In the nine patients with ARDSexp airway cultures were positive in three; these three also had positive blood cultures. Of the nine patients with ARDSexp, seven had undergone surgery 10 ± 7 d before the study.
| Patient No. | Diagnosis | Airway Cultures | Blood Cultures | Abdominal Cultures | Days from Intubation/ ARDS Onset* | Survived/Died | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ARDSp | ||||||||||||
| 1 | Pneumonia | Legionella † | — | — | 3/0 | D | ||||||
| 2 | Pneumonia‡ | — | — | — | 1/0 | S | ||||||
| 3 | Pneumonia | Candida | — | — | 1/0 | S | ||||||
| 4 | Hemorrhagic alveolitis | — | — | — | 3/2 | S | ||||||
| 5 | Pneumonia | Klebsiella | — | — | 0/0 | D | ||||||
| 6 | Pneumonia | Klebsiella | — | — | 3/1 | S | ||||||
| Enterobacter | ||||||||||||
| 7 | Pneumonia | Cytomegalovirus | — | — | 8/2 | D | ||||||
| 8 | Pneumonia | Pneumocystis | — | — | 0/0 | D | ||||||
| Aspergillus | ||||||||||||
| Staph. aureus | ||||||||||||
| 9 | Pneumonia | Legionella † | — | — | 1/0 | S | ||||||
| 10 | Pneumonia | Candida | — | — | 1/1 | D | ||||||
| 11 | Pneumonia | Pseudomonas | — | — | 5/4 | S | ||||||
| 12 | Pneumonia | Pneumocystis | — | — | 2/1 | S | ||||||
| ARDSexp | ||||||||||||
| 1 | Polytrauma | — | — | — | 3/0 | D | ||||||
| 2 | Polytrauma | Staph. aureus | Staph. aureus | Staph. aureus | 0/0 | D | ||||||
| Enterobacter | Enterobacter | |||||||||||
| Bacteroides | ||||||||||||
| 3 | Intestinal | — | — | — | 1/0 | S | ||||||
| Infarction | ||||||||||||
| 4 | Polytrauma | Pseudomonas | Candida | — | 0/0 | S | ||||||
| 5 | Peritonitis | — | — | — | 3/0 | D | ||||||
| 6 | Peritonitis | Pseudomonas | Staph. aureus | Staph. aureus | 1/0 | S | ||||||
| 7 | Hemorrhagic shock | — | — | — | 3/2 | S | ||||||
| 8 | Peritonitis | — | — | Enterobacter | 1/0 | S | ||||||
| Bacteroides | ||||||||||||
| 9 | Intestinal | — | — | — | 12/3 | D | ||||||
| infarction |
Every patient had an arterial cannula, a Swan-Ganz pulmonary- artery catheter and a urinary catheter inserted for clinical monitoring. The Simplified Acute Physiology Score (SAPS) (5) and the number of organ dysfunctions (6) were recorded on the day of the study. The characteristics of the patients population are summarized in Table 2.
| Both Groups (n = 21) | Group 1 ARDSp(n = 12) | Group 2 ARDSexp(n = 9) | p Value | |||||
|---|---|---|---|---|---|---|---|---|
| Sex, M/F | 14/7 | 8/4 | 6/3 | NS | ||||
| Age, yr | 46.0 ± 18.9 | 38.6 ± 13.5 | 55.9 ± 21.3 | < 0.05 | ||||
| Height, cm | 172.9 ± 10.0 | 172.3 ± 8.2 | 173.7 ± 12.6 | NS | ||||
| Weight, kg | 69.7 ± 15.7 | 70.4 ± 13.7 | 68.8 ± 18.7 | NS | ||||
| SAPS | 11.8 ± 4.3 | 10.8 ± 4.5 | 13.2 ± 3.9 | NS | ||||
| MOF, n | 2.9 ± 1.3 | 2.8 ± 1.2 | 3.3 ± 1.4 | NS | ||||
| Days before the study | 2.5 ± 2.9 | 2.3 ± 2.3 | 2.7 ± 2.7 | NS | ||||
| Mortality, S/D | 11/10 | 6/6 | 5/4 | NS | ||||
| ICU Stay, d | 21.7 ± 14.9 | 18.2 ± 9.7 | 26.4 ± 19.5 | NS |
In all patients while in the supine position, we measured the elastic properties of the lung and chest wall (in triplicate), the end-expiratory lung volume (EELV), and the intra-abdominal pressure at four different PEEP levels (0, 5, 10, and 15 cm H2O) applied in random order. The other ventilator settings were kept constant throughout the entire protocol, which lasted between 25 and 30 min.
All the patients were ventilated with a Siemens Servo 900 C ventilator in the volume control mode with constant inspiratory flow (Table 3). The patients of both groups were ventilated following the guidelines recommended by the American College of Chest Physicians (7). Before the investigation, the patients were sedated with fentanyl (2 to 3 μg/kg) and diazepam (0.1 to 0.2 mg/kg), and paralyzed with pancuronium bromide (0.1 to 0.2 mg/kg).
| Both Groups (n = 21) | Group 1 ARDSp(n = 12) | Group 2 ARDSexp(n = 9) | p Value | |||||
|---|---|---|---|---|---|---|---|---|
| Vt, L | 0.688 ± 0.142 | 0.686 ± 0.129 | 0.692 ± 0.166 | NS | ||||
| V˙, L/s | 0.493 ± 0.082 | 0.507 ± 0.092 | 0.475 ± 0.068 | NS | ||||
| V˙ e, L/min | 9.88 ± 2.05 | 9.39 ± 1.89 | 10.60 ± 2.20 | NS | ||||
| RR, breaths/min | 14.5 ± 2.7 | 14.0 ± 2.5 | 15.3 ± 3.1 | NS | ||||
| PEEP, cm H2O | 10.4 ± 4.0 | 10.9 ± 3.2 | 9.7 ± 4.9 | NS | ||||
| Fi O2 , % | 77 ± 20 | 80 ± 21 | 74 ± 19 | NS | ||||
| PaO2 , mm Hg | 97.8 ± 20.6 | 91.7 ± 20.4 | 105.9 ± 18.9 | NS | ||||
| PaCO2 , mm Hg | 46.3 ± 8.7 | 48.3 ± 9.6 | 43.6 ± 6.9 | NS | ||||
| pH | 7.34 ± 0.09 | 7.32 ± 0.09 | 7.37 ± 0.08 | NS | ||||
| PaO2 /Fi O2 | 134.8 ± 42.0 | 123.8 ± 45.3 | 149.4 ± 34.4 | NS | ||||
| HR, beats/min | 21.7 ± 14.9 | 116.6 ± 17.5 | 110.8 ± 22.4 | NS | ||||
| Pa, mm Hg | 83.0 ± 15.1 | 84.5 ± 14.9 | 82.3 ± 26.7 | NS | ||||
| Ppa, mm Hg | 28.6 ± 5.6 | 28.2 ± 6.3 | 29.3 ± 4.6 | NS | ||||
| Ppao, mm Hg | 13.7 ± 4.7 | 13.9 ± 4.8 | 13.3 ± 4.8 | NS | ||||
| Pcv, mm Hg | 9.0 ± 4.3 | 8.1 ± 4.2 | 10.0 ± 4.5 | NS | ||||
| CI, L/min/m2 | 4.1 ± 1.8 | 4.6 ± 1.4 | 3.8 ± 1.7 | NS | ||||
| WB, L/d | −0.385 ± 1.836 | −0.220 ± 0.905 | −0.590 ± 2.701 | NS |
Respiratory mechanics were assessed as previously reported (8). Airway pressure (Pao) and gas flow were measured and recorded by a computerized system (CP-100 Pulmonary Monitor; Bicore Monitoring System, Irvine, CA) at the endotracheal tube opening. Esophageal pressure (Pes) was determined from an esophageal balloon inflated with 0.5-1 ml of air, positioned at the lower third of the esophagus, as confirmed by the chest roentgenograph. The validity of Pes was verified by the “occlusion test” according to the principle of Baydur and colleagues (9). Volume was obtained by digital integration of the flow signal.
We recorded Pao and Pes during a 3 to 4 s airway occlusion at end- expiration and at end-inspiration. Static elastance of the total respiratory system (Est,rs) was computed as Est,rs = DPao/Vt, where DPao is the difference between end-inspiratory and end-expiratory airway pressure and Vt is the tidal volume. Static elastance of the chest wall (Est,w) was computed as DPes/Vt, where DPes 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). End-expiratory volume corresponded to the elastic equilibrium volume in each patient, as evidenced by zero flow during an expiratory pause and absence of changes in Pao after airway occlusion.
Maximal (Rmax,rs) and minimal (Rmin,rs) resistances 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 corrected for the tube resistance, P1 is the pressure recorded after the immediate drop from Pmax, P2 is the plateau pressure and V˙ is the flow immediately 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) caused by stress relaxation and/or time-constant inequalities within the respiratory system tissues. Because there was no appreciable drop in Pes immediately after the occlusion (i.e., P1 in the esophageal tracings was not identifiable), Rmin,rs reflects essentially airway resistance (Rmin,L), and minimal chest wall resistance (Rmin,w) can be considered negligible. As a consequence, maximal 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 of Rmin,L + DR,L gives the maximal lung resistance (Rmax,L).
EELV was measured at zero end-expiratory pressure (ZEEP) using a closed-circuit helium dilution method (10). To compute EELV at each level of PEEP, we measured the total exhaled volume after PEEP removal during an expiratory period long enough to reach zero flow. This total exhaled volume represented the volume of the lung above the EELV at ZEEP, at the end of tidal inspiration. Therefore, EELV was computed as: EELV at ZEEP + (total exhaled volume − tidal volume).
To estimate the lung recruitment by PEEP, we had to differentiate, in the measured lung volume, the component caused by the inflation of pulmonary units already open and the component caused by the recruitment of previously collapsed pulmonary units. To do so we assumed that pulmonary units open at ZEEP inflate with tidal volume or PEEP according to the elastance present at ZEEP (predicted volume). This was calculated by adding to EELV the amount expected to be gained with PEEP according to the elastance (DPao/Vt) determined at ZEEP. Lung volume recruitment was then computed as measured minus predicted volume, i.e., EELV at PEEP − (EELV at ZEEP + PEEP/Est,rs at ZEEP).
The basic assumption for this estimate of alveolar recruitment relies on the finding that specific elastance of pulmonary units in ARDS is near to normal (3, 11), indicating that the elastance decrease with PEEP is likely due to the recruitment of the new pulmonary units. This assumption has been adopted by other investigators also (12).
Intra-abdominal pressure was measured using a transurethral bladder catheter (13). One hundred milliliters of normal saline were infused through the urinary catheter into the bladder. The catheter was then clamped and the intra-abdominal pressure was recorded by a pressure transducer as mean pressure at end-expiration. Zero was set at the level of the pubis.
Data are expressed as mean ± standard deviation (SD), unless otherwise specified. In each group, statistical comparisons between PEEP levels were done using analysis of variance (ANOVA). Individual comparisons (ZEEP versus PEEP) were obtained using Student's paired t test. Individual comparisons between the two groups, at each level of PEEP, were performed using Student's unpaired t test. Bonferroni's correction for multiple comparisons was applied.
The anthropometric characteristics, number of organ dysfunctions, acute physiology score, and outcome for all patients are summarized in Table 2. We found no differences in any variable between the ARDSp or ARDSexp groups, except for age, which was significantly lower in the patients with ARDSp. Similarly, as shown in Table 3, no differences were noted for the ventilatory setting, gas exchange, and hemodynamic variables measured before the PEEP trial. The average daily water balance from the onset of ARDS to the day of the study was also similar between the ARDSp and the ARDSexp groups.
The total population. The high values of Est,rs and Est,L, the moderate increase in Est,w, and low EELV are typical of ARDS (Table 4). When PEEP was increased from 0 to 15 cm H2O, Est,rs and Est,L did not change significantly, Est,w decreased slightly, and intra-abdominal pressure increased by an average of 1.8 ± 1.7 cm H2O. As expected, EELV increased significantly with PEEP.
| PEEP (cm H2O) | ||||||||
|---|---|---|---|---|---|---|---|---|
| 0 | 5 | 10 | 15 | |||||
| Est,rs, cm H2O/L | 25.7 ± 5.7 | 24.9 ± 6.9 | 24.4 ± 7.2 | 27.0 ± 10.3 | ||||
| Est,L, cm H2O/L | 17.5 ± 6.0 | 17.7 ± 7.3 | 17.6 ± 8.2 | 20.0 ± 11.7 | ||||
| Est,w, cm H2O/L | 8.2 ± 4.5† | 7.2 ± 4.4‡ | 6.8 ± 4.1‡ | 7.0 ± 3.7‡ | ||||
| EELV, L | 0.576 ± 0.264† | 0.798 ± 0.321‡ | 1.049 ± 0.377† | 1.297 ± 0.383‡ | ||||
| IAP, cm H2O | 14.4 ± 8.2† | 14.8 ± 7.9 | 14.8 ± 8.1 | 16.1 ± 8.6‡ | ||||
ARDS of pulmonary versus extrapulmonary origin at ZEEP. As shown in Figure 1, Est,rs was similar for both types of ARDS at ZEEP (25.4 ± 6.2 versus 26 ± 5.4 cm H2O/L, p = NS), but Est,L was higher in ARDSp (20.2 ± 5.4 versus 13.8 ± 5.0 cm H2O/L in ARDSexp, p < 0.01) indicating a stiffer lung. Est,w was more than twofold higher in ARDSexp than in ARDSp (12.1 ± 3.8 versus 5.2 ± 1.9 cm H2O/L, p < 0.01), indicating a stiffer chest wall. This latter finding was possibly due to higher intra-abdominal pressure, which amounted to 22.2 ± 6.0 and 8.5 ± 2.9 cm H2O in ARDSexp and ARDSp, respectively (p < 0.01). The close correctional between Est,w and intra-abdominal pressure is shown in Figure 2.
Fig. 1. Changes of static elastances of the respiratory system (Est,rs), lung (Est,L), and chest wall (Est,w) as a function of PEEP in patients with ARDS caused by pulmonary disease (Group 1, top panel ) with in ARDS caused by extrapulmonary disease (Group 2, bottom panel ). Comparison within each group: *p < 0.05 versus PEEP 0 cm H2O; **p < 0.01 versus PEEP 0 cm H2O. Comparison between the two groups; ▴p < 0.05 versus Group 1; ▴▴p < 0.01 versus Group 1.
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Fig. 2. Chest wall static elastance (Est,w) as a function of intra-abdominal pressure (IAP), Solid circles refer to patients of Group 1 (ARDS caused by pulmonary disease); open circles refer to patients of Group 2 (ARDS from extrapulmonary disease). Regression equation: Est,w = 1.65 ± 0.46* AP; r = 0.84, p < 0.01.
[More] [Minimize]Because the fluid management in the individual patients might account for the differences we found in respiratory system mechanics, we looked for a possible relationship between mechanics of the total respiratory system, lung, and chest wall and IAP versus the daily fluid balance of the day of the study, the cumulative fluid balance of the 48 h before the study, and the cumulative fluid balance from the day of intubation and the day of ARDS onset to the day of the study. None of these relationships reached statistical significance.
PEEP response in ARDS of pulmonary or extrapulmonary origin. Increasing PEEP from 0 to 15 cm H2O led to opposite effects on elastance in the two types of ARDS, as shown in Figure 1. In ARDSp (upper panel), increasing PEEP caused an increase of Est,rs mainly caused by an increase in Est,L whereas in ARDSexp (lower panel) PEEP resulted in a significant decrease in Est,rs caused by the reduction in both Est,L and Est,w. Increasing PEEP from 0 to 15 cm H2O led to a slight increase in intra-abdominal pressure (p < 0.01) in both groups and amounted, at 15 cm H2O PEEP, to 10.0 ± 3.4 and 24.3 ± 6.1 cm H2O in ARDSp and ARDSexp, respectively. These results indicate a stiffer lung in ARDSp, which does not improve with PEEP, while in ARDSexp there is a stiffer thoracoabdominal cage and a more compliant lung, which both improve with increasing PEEP. As shown in Figure 3 (left panel), the pressure-volume relationship of the total respiratory system of patients with ARDSp was essentially the same at each PEEP level. This suggests that, at end-expiration, PEEP keeps already open pulmonary units more inflated, but no recruitment occurs. This pattern is substantially different in ARDSexp (right panel) where an upwards shift of the pressure-volume curve of the total respiratory system was observed, indicating significant recruitment of pulmonary units by PEEP. The difference in response between ARDSp and ARDSexp with regard to end-expiratory lung volume and recruitment is shown in Table 5.
Fig. 3. Pressure-volume (P-V) relationship in patients with ARDS caused by pulmonary disease, (Group 1, left panel ) and with ARDS caused by extrapulmonary disease (Group 2, right panel ) as a function of PEEP. As shown, in Group 1, the P-V relationships follow systematically the same line, with a slope decreasing at 15 cm H2O (i.e., decreased compliance), whereas the P-V relationships of Group 2 patients are shifted upwards as a function of PEEP (i.e., at the same pressure of volume is greater at higher PEEP, suggesting recruitment). The slope of P-V relationship increases with PEEP, indicating the compliance improvement. Data are presented as mean ± standard error.
[More] [Minimize]| PEEP (cm H 2 O) | ||||||||
|---|---|---|---|---|---|---|---|---|
| 0 | 5 | 10 | 15 | |||||
| EELV, L | ||||||||
| ARDSp | 0.556 ± 0.254† | 0.762 ± 0.319‡ | 0.970 ± 0.381‡ | 1.150 ± 0.356‡,§ | ||||
| ARDSexp | 0.602 ± 0.291† | 0.847 ± 0.338‡ | 1.155 ± 0.367‡ | 1.494 ± 0.340‡ | ||||
| Estimated recruitment, L | ||||||||
| ARDSp | −0.002 ± 0.088 | −0.003 ± 0.098§ | −0.031 ± 0.092‖ | |||||
| ARDSexp | 0.043 ± 0.120† | 0.153 ± 0.200** | 0.293 ± 0.241†,† | |||||
Resistance of the total respiratory system, lung, and chest wall. In Table 6 are summarized, for the whole population, the resistances (“ohmic” and additional) of the total respiratory system, lung, and chest wall as a function of PEEP. As shown, we observed a significant decrease with PEEP of the “ohmic” resistance, whereas DR,rs significantly increased mainly because of the lung component.
| PEEP (cm H2O) | ||||||||
|---|---|---|---|---|---|---|---|---|
| 0 | 5 | 10 | 15 | |||||
| Rmax,rs, cm H2O/L/s | 10.4 ± 2.6 | 10.7 ± 3.0 | 10.8 ± 4.1 | 13.2 ± 6.4 | ||||
| Rint,rs, cm H2O/L/s | 4.7 ± 2.0† | 4.6 ± 2.2 | 3.2 ± 2.0§ | 2.9 ± 2.1§ | ||||
| Rmax,L, cm H2O/L/s | 7.8 ± 2.8 | 8.1 ± 2.8 | 8.2 ± 3.8 | 10.3 ± 6.8 | ||||
| DR,rs, cm H2O/L/s | 5.7 ± 2.0† | 6.1 ± 2.2 | 7.6 ± 3.3‡ | 10.3 ± 5.7§ | ||||
| DR,L, cm H2O/L/s | 3.1 ± 1.5† | 3.5 ± 1.9 | 4.9 ± 3.1‡ | 7.4 ± 6.0§ | ||||
| DR,w, cm H2O/L/s | 2.6 ± 1.6 | 2.6 ± 1.7 | 2.6 ± 1.8 | 2.9 ± 1.8 | ||||
This pattern was somewhat different in ARDSp versus ARDSexp. As shown in Figure 4, with PEEP, Rmax,rs increased significantly in ARDSp, but it remained constant in ARDSexp. As in both groups the “ohmic” resistances decreased significantly, the major difference between the two types of ARDS was a clear increase in DR,L with PEEP in the former, whereas in the latter DR,L remained immodified. The DR,w was higher in ARDSexp and correlated with the IAP (r = 0.66, p < 0.01).
Fig. 4. “Ohmic” resistance of the respiratory system (Rint,rs), additional resistance of the lung (DR,L), and additional resistance of the chest wall (DR,w) as a function of PEEP in patients with ARDS caused by pulmonary disease (Group 1, left panel ) and in patients with ARDS caused by extrapulmonary diseases (Group 2, right panel ). The total column represents the total resistance of the respiratory system (Rmax,rs). Values expressed as mean ± standard error. Symbols outside the column represent statistics for Rmax,rs.
[More] [Minimize]The main finding of the present study is a different response of respiratory mechanics in ARDS of pulmonary versus extrapulmonary origin. This may correspond to different underlying pathology resulting from two different pathogenetic pathways (4): a “direct” insult to the lung parenchyma in ARDS caused by pulmonary disease such as diffuse pneumonia versus an “indirect” insult to the lung parenchyma in ARDS caused by extrapulmonary disease such as abdominal sepsis or pancreatitis. The prevalent pathogenetic pathway has never been considered in clinical studies on ARDS; patients with both types of ARDS are usually grouped together. Our findings suggest that this differentiation may be important.
The distinction between pulmonary and extrapulmonary origins of ARDS seems not to be controversial nor difficult, since the three physicians who independently classified our study population agreed in all cases but one, an allergic-hemorrhagic alveolitis, finally classified as pulmonary ARDS. The distinction may be more difficult if there is an overlap of the two mechanisms, as in ARDS from peritoneal sepsis with later pulmonary superinfection. As this difficulty can increase with time, we limited our study to the early phases of ARDS. Our two groups included primarily diffuse pneumonia as pulmonary ARDS and abdominal sepsis as extrapulmonary ARDS, as we did not observe in this study population other etiologies that might possibly lead to “direct” or “indirect” lung injury such as near drowning, aspiration, meningitis, etc. The etiologies we observed in our patients, however, cover the majority of ARDS cases commonly presenting in intensive care units (1, 2).
In the total population, at ZEEP, the low end-expiratory lung volume (0.576 ± 0.264 L) and the high Est,rs (25.7 ± 5.7 cm H2O/L) were typical of ARDS.
It is traditionally thought that in ARDS the high Est,rs is mainly due to the lung component, with the assumption that Est,w is normal. This assumption, however, is not correct, since the few studies that have specifically addressed this question found a consistent increase in Est,w, ranging from 7.2 to 15 cm H2O/L (normal values, 3.0 to 5.0 cm H2O/L) (10, 14– 17). In the total population our Est,w values (8.2 ± 4.5 cm H2O/L) are in the range of those reported previously. However, in ARDS caused by pulmonary disease Est,w was normal (5.2 ± 1.9 cm H2O/L), whereas in ARDS secondary to an extrapulmonary cause Est,w was markedly elevated (12.1 ± 3.8 cm H2O/L).
We cannot rule out, however, a possible role of age to explain the differences in lung and chest wall elastance we observed between the two groups. The ARDSexp patients, in fact, were 17.3 yr older than the ARDSp patients. In normal subjects the elastance of the respiratory system increases with age, and this increase results from a decreased Est,L (0.1 to 0.2 cm H2O/yr loss of recoil at total lung capacity), which is offset by the increase of Est,w (18). However, in our study population we did not find any relationship between age and Est,rs (r = 0.11). Moreover, the differences in Est, L and Est,w we found between the two groups, largely exceed the possible age-related differences (19). (In 38 normal preoperative anesthetized-paralyzed supine patients 13 to 94 yr of age, we found a significant increase of Est,w with age according to the following equation [unpublished data]: Est,w [cm H2O/L] = 3.65 + 0.04 × age [yr], r = 0.57; p < 0.01. This accounts for a “physiologic” increase of Est,w of only 0.69 cm H2O/L over 17.3 yr of age difference.)
Our findings suggest that in ARDS the increased Est,rs is produced by two different mechanisms: in ARDS caused by a direct pulmonary insult, a high Est,L is the major component (ratio Est,L/Est,rs = 0.79 ± 0.07), whereas in ARDS caused by extrapulmonary disease, increased Est,L and Est,w equally contribute to the high Est,rs (ratio Est,L/Est,rs = 0.53 ± 0.15).
The mean IAP was threefold greater in ARDS of extrapulmonary than of pulmonary origin, and it appears closely related to Est,w (Figure 2). A similar correlation has been observed both in animal models (20) and in normal subjects when IAP was altered artificially (21). In critically ill patients, data on IAP are surprisingly rare. In our patients, the elevated values can be explained, in most patients, by primary abdominal disease or edema of the gastrointestinal tract after shock or trauma.
The resistance of the chest wall was also elevated in ARDS because of extrapulmonary causes and significantly related to IAP, suggesting that IAP affects the viscoelastic properties of the thoracoabdominal region.
In summary, although at ZEEP ARDS of both origins have an equal increase of Est,rs, in ARDS caused by pulmonary disease this is primarily due to an altered Est,L, whereas in ARDS caused by extrapulmonary disease, Est,L is less affected, and Est,w and IAP are markedly increased.
For the total patient population, no significant changes in Est,rs with PEEP were seen. Other groups have reported an increase (14, 16), decrease (15, 22), or no change (10, 23) in Est,rs with PEEP. These apparently contradictory findings may be due to different proportions in each study of patients with ARDS caused by pulmonary or extrapulmonary diseases. The two types of ARDS, in fact, show opposite responses to PEEP; patients with direct lung injury significantly increase Est,rs, mainly the Est,L component, whereas in secondary lung injury PEEP decreases Est,rs and both of its components, Est,L and Est,w.
It is known that in the early phases of ARDS, PEEP regionally stretches the pulmonary units that are already open, i.e., increases elastance. PEEP simultaneously maintains open, at end-expiration, the pulmonary units, which collapse at lower pressure, i.e., increases the number of open units, thereby decreasing Est,rs (24). The global variations of Est,rs depend on the prevalence in a given lung of each of these two mechanisms. The global variations of Est,rs with PEEP, found in ARDS caused by pulmonary disease, suggest the prevalence of stretching phenomena, whereas the decrease of Est,rs in ARDS from extrapulmonary disease indicates a prevalence of recruitment of previously closed alveolar spaces.
The decrease of Est,w with PEEP in extrapulmonary ARDS may be due to a greater increase in lung volume, which may place the thoracic cage in a more favorable part of its pressure-volume curve.
Airway resistance decreased in both groups, as expected, probably because of the increase in lung volume induced by PEEP (10). However, the DR,L markedly increased with PEEP in ARDS caused by pulmonary disease, where stretching phenomena seem prevalent. Although the physiologic meaning of DR,L is still unclear, these data suggest that stretching may affect the viscoelastic resistance of the lung tissue.
In this study, we explored the PEEP level up to 15 cm H2O. We cannot exclude that higher levels of PEEP and inspiratory plateau pressure could result in recruitment in pulmonary ARDS and in further recruitment in extrapulmonary ARDS. However, while this possibility is likely in extrapulmonary ARDS, it seems unlikely in pulmonary ARDS, where stretching phenomena (i.e., an increase in Est,rs and Est,L) are evident already at 15 cm H2O PEEP (see Figure 3).
There is a general belief that ARDS is the extreme form of a spectrum of lung injury caused by a uniform inflammatory mechanism that is independent of the precipitating disease. This assumption mainly originates from pathology studies, which have consistently indicated that the lung response to injury is stereotyped, with transition from acute alveolar capillary damage to a late proliferative phase, quite independently of the initial cause (25). Unfortunately, most of the studies report late or terminal events, and pathologic features of early phases of ARDS such as interstitial edema and alveolar collapse are not easily recognized unless special techniques are used for obtaining lung specimens and processing the tissue.
In experimental ARDS, different lung responses have been reported when the injury is applied directly to the alveoli, as with intratracheal instillation of endotoxin (26, 27), complement (28), tumor necrosis factor (29), or bacteria (30), or when the lung is injured indirectly by a toxic substance injected intravenously (31) or intraperitoneally (32). After a “direct” insult the alveolar damage includes edema, fibrin, collagen, neutrophil aggregates, and red cells seen in the alveoli, whereas the “indirect” insult results in a prevalent microvascular congestion, interstitial edema and less severe alveolar damage such as typically seen after intravenously administered Escherichia coli endotoxin (33). The pathologic differences between “direct” and “indirect” insult are well illustrated in models where the two types of insult can be observed (34, 35). “Direct” injury by live bacteria causes intra-alveolar damage with loss of compartmentalization (29) in the instilled regions, whereas in lung areas not directly instilled, vascular congestion and interstitial edema are noted. If pulmonary lesions in human ARDS are similar to those observed in animal models, prevalent consolidation is expected in “direct” injury type ARDS, and prevalent interstitial edema and alveolar collapse in “indirect” injury type ARDS. These pathologic mechanisms may explain our data: lung volume recruitment is marginal when the underlying pathology is prevalent consolidation, whereas in ARDS caused by extrapulmonary diseases, recruitment by PEEP is remarkable, possibly because of prevalent interstitial edema and alveolar collapse. The morphologic data reported by Lamy and colleagues (36) are in line with our interpretation. In patients in whom gas exchange did not improve with PEEP in early ARDS, severe lung tissue damage was seen, with alteration of alveolar spaces by hemorrhage and purulent exudate, whereas the responders to PEEP had less severe lung damage but diffuse congestion, microatelectasis, and some alveolar damage.
It is possible that these different responses to PEEP disappear in late ARDS where the lung structure undergoes important changes such as remodeling the fibrosis (37, 38).
We believe that the recognition of the two forms of ARDS, pulmonary and extrapulmonary, may lead to an improved clinical management.
Two major complications of positive pressure ventilation in patients with ARDS are barotrauma and hemodynamic impairment, both related to the elevated Est,rs. We can speculate that for a similar Est,rs, the differences between Est,L and Est,w between pulmonary and extrapulmonary ARDS identify the former at a greater risk of barotrauma and the latter at a greater risk of hemodynamic impairment. High Est,L and low Est,w in pulmonary ARDS, in fact, result in elevated transmural pressure, a risk factor for barotrauma, and low pleural pressure, whereas lower Est,L and Higher Est,w in extrapulmonary ARDS result in elevated pleural pressure, with consecutive possible impairment of venous return, cardiac filling, and cardiac output. The lack of recruitment with PEEP we observed in ARDS from pulmonary disease does not necessarily imply that PEEP is unuseful in this type of ARDS. PEEP may, in fact, improve gas exchange through mechanisms other than recruitment as regional diversion of ventilation or perfusion (39).
Finally, our data suggest, in agreement with recent work (40, 41), the importance of respiratory mechanics partitioning for a better characterization of ARDS underlying pathology and for a possible improvement in the clinical management.
Supported in part by Grant No. 32.043637.95 from the Swiss National Research Foundation to P. M. Suter.
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