American Journal of Respiratory and Critical Care Medicine

A prospective, crossover, physiologic study was performed in 10 patients with acute lung injury to assess the respective short-term effects of noninvasive pressure-support ventilation and continuous positive airway pressure. We measured breathing pattern, neuromuscular drive, inspiratory muscle effort, arterial blood gases, and dyspnea while breathing with minimal support and the equipment for measurements, with two combinations of pressure-support ventilation above positive end-expiratory pressure (10–10 and 15–5 cm H2O), and with continuous positive airway pressure (10 cm H2O). Tidal volume was increased with pressure support, and not with continuous positive airway pressure. Neuromuscular drive and inspiratory muscle effort were lower with the two pressure-support ventilation levels than with other situations (p < 0.05). Dyspnea relief was significantly better with high-level pressure-support ventilation (15–5 cm H2O; p < 0.001). Oxygenation improved when 10 cm H2O positive end-expiratory pressure was applied, alone or in combination. We conclude that, in patients with acute lung injury (1) noninvasive pressure-support ventilation combined with positive end-expiratory pressure is needed to reduce inspiratory muscle effort; (2) continuous positive airway pressure, in this setting, improves oxygenation but fails to unload the respiratory muscles; and (3) pressure-support levels of 10 and 15 cm H2O provide similar unloading but differ in their effects on dyspnea.

In selected patients with acute lung injury (ALI) (1), early institution of noninvasive mechanical ventilation (NIV) may reverse the acute episode, obviating endotracheal intubation (2, 3). Nevertheless, switching to invasive ventilation is required in more than 40 to 50% of hypoxemic patients receiving NIV in observational studies (47). Physiologic data are needed to assist in optimizing NIV strategies for patients with ALI. On the one hand, ventilatory support set too high may cause excessive leakage and thus complicate NIV management and produce ineffective efforts and patient–ventilator asynchrony; on the other hand, however, insufficient support may translate into insufficient inspiratory muscle unloading.

Applying positive end-expiratory pressure (PEEP) to the airway opening has been shown to lessen the reduction in functional residual capacity (FRC) and to improve respiratory mechanics and gas exchange (3). These data have led intensive care unit physicians to use continuous positive airway pressure (CPAP) as a means of preventing subsequent clinical deterioration and reducing the need for endotracheal intubation (811). Nevertheless, clinical data do not strongly support the use of CPAP in patients with ALI (12), and the better outcomes reported with other forms of noninvasive ventilation may be ascribable to the combined use of pressure-support ventilation (PSV) and PEEP (1317).

This study compared the short-term physiologic effects of two combinations of PSV above PEEP and of CPAP alone, in terms of breathing pattern, respiratory drive, inspiratory muscle effort, oxygenation, and dyspnea relief in patients with ALI treated by NIV. One important reason for the study was to distinguish the physiologic reasons that may underlie the discrepancies in terms of clinical outcome between these two NIV modalities. The other objective was to help clinicians at finding the best combination of inspiratory and expiratory pressures.

This study has been presented in abstract form (18).

An expanded Methods is available on the online supplement. The appropriate institutional review board approved the study, and informed consent was obtained for all patients.

Patients

Ten patients with ALI were enrolled (Table 1)

TABLE 1. Patient characteristics


Patient No.

Age (yr)

Sex (M/F)

SAPS II

Main Diagnosis

Chronic Heart
 Disease

Survival
 137M29ARDS/Pneumocystis carinii pneumoniaNoYes
 277M29ARDS/CAPNoNo
 375F27ARDS/CAPNoNo
 478F70ARDS/aspirationNoNo
 573M33ARDS/nosocomial pneumoniaNoYes
 642M35ALI/CAPNoYes
 769F22ALI/CAPYesYes
 864M53ARDS/eosinophilic pneumoniaYesNo
 961M34ARDS/CAPYesYes
1036F36ARDS/aspirationNoYes
Overall
61 ± 17
6 M/4 F
41 ± 17
8 ARDS/2 ALI
30%
60%

Definition of abbreviations: ALI = acute lung injury; ARDS = acute respiratory distress syndrome; CAP = community-acquired pneumonia; F = female; M = male; SAPSII = Simplified Acute Physiologic Score II.

. Inclusion criteria were as follows: acute respiratory insufficiency (PaO2/FiO2 ⩽ 300 mm Hg under oxygen), bilateral lung infiltrates by chest radiograph, and clinical indication for NIV. Exclusion criteria were as follows: age younger than 18 yr, chronic CO2 retention, systolic blood pressure of less than 90 mm Hg, ventricular arrhythmia, encephalopathy or coma, life-threatening hypoxemia (SpO2 ⩽ 80% under oxygen, or ⩽ 92% under NIV), and inability to clear secretions. All patients received NIV within the 12 h before inclusion (Evita 4; Dräger, Lübeck, Germany). Tables 2 and 3

TABLE 2. Respiratory pattern and hemodynamic parameters during the five study periods


Variable

Initial*

CPAP

PSV10/PEEP10

PSV15/PEEP5

Final||
VTe, Ml524 ± 212394 ± 224483 ± 247591 ± 279§535 ± 229
RR, breaths/min29 ± 1028 ± 1128 ± 1126 ± 930 ± 12
V̇E, L/min15.7 ± 4.412.3 ± 3.414.6 ± 3.817.6 ± 5.415.6 ± 5.3
Leaks, %25 ± 1339 ± 1836 ± 1837 ± 2224 ± 15
MAP, mm Hg77 ± 1379 ± 1677 ± 1675 ± 1684 ± 17
HR, beats/min
100 ± 13
100 ± 9
95 ± 14
96 ± 16
99 ± 14

*Initial indicates parameter value measured during the initial baseline.

p ⩽ 0.05 compared with initial baseline.

p ⩽ 0.005 compared with CPAP.

§p ⩽ 0.05 compared with PSV10/10.

||Final indicates parameter value measured after the randomized sequences and return to the baseline condition.

Definition of abbreviations: CPAP = continuous positive airway pressure; HR = heart rate; MAP = mean arterial pressure; PEEP = positive end-expiratory pressure; PSV = pressure-support ventilation; RR = respiratory rate; VTe = expiratory VT.

TABLE 3. Arterial blood gases during the five study periods


Variable

Initial*

CPAP

PSV10/PEEP10

PSV15/PEEP5

Final
pH7.37 ± 0.107.36 ± 0.127.39 ± 0.087.40 ± 0.08§7.38 ± 0.10
PaO2/FIO2 mm Hg131 ± 61184 ± 74206 ± 120153 ± 41||169 ± 83
PaCO2, mm Hg
42.0 ± 11.3
44.4 ± 17.8
40.2 ± 14.3
38.6 ± 12.3§
42.2 ± 14.4

*Initial indicates parameter value measured during the initial baseline

p ⩽ 0.05 compared with initial baseline.

p ⩽ 0.005 compared with initial baseline.

§p ⩽ 0.05 compared with CPAP.

||p ⩽ 0.05 compared with PSV10/PEEP10.

Final indicates parameter value measured after the randomized sequences and return to the baseline condition.

Definition of abbreviations: CPAP = continuous positive airway pressure; PEEP = positive end-expiratory pressure; PSV = pressure-support ventilation.

show baseline parameters.

Measurements

Flow was measured using a Fleisch no.1 pneumotachograph (Metabo, Epalinges, Switzerland), connected to a pressure transducer (MP45; Validyne, Northridge, CA) located between the mask and the Y connector. Airway pressure (Paw) was measured between the ventilator and the pneumotachograph. Esophageal (Pes) and gastric (Pga) pressures were measured using a double-balloon catheter (Marquat, Boissy-Saint Léger, France). Correct catheter placement was checked using standard methods (19, 20). Respiratory center output was estimated based on the Pes decrease at 100 ms (P0.1) (21). Dyspnea was assessed by asking the patients to grade treatment effects versus initial baseline as follows: +2, marked improvement; +1, slight improvement; 0, no change; −1, slight deterioration; and −2, marked deterioration.

Initial measurements were performed while the patient was breathing spontaneously through the ventilator circuit and measuring equipment. Such equipment is needed to deliver ventilatory assistance, but increases breathing effort by imposing apparatus dead space and circuit resistance during spontaneous breathing, and could lead to overestimating the patient's effort during initial and final baseline periods. To estimate as closely as possible spontaneous breathing, a small PSV level was individually titrated to compensate for the work imposed by the circuit (3–5 cm H2O). Recordings were performed during three periods, in random order, followed by a return to a final condition similar to the initial: (1) CPAP, 10 cm H2O; (2) PSV, 10 cm H2O above a PEEP of 10 cm H2O (PSV10/PEEP10); and (3) PSV, 15 cm H2O above a PEEP of 5 cm H2O (PSV15/PEEP5).

Data Analysis and Assessment of Patient's Effort

Because of leaks, expired Vt was considered closer to the true Vt taken by the patient and was used for data analysis. The patient's inspiratory work of breathing (WOB) was computed from Pes and Vt loops, as previously described (21). Inspiratory WOB was calculated by applying a correcting factor to the inspiratory flow, based on the expired/inspired Vt ratio (22).

Any difference between initial Pes and the zero-flow point indicated intrinsic PEEP (21). This intrinsic PEEP value was corrected for expiratory muscle activity, as detected on Pga tracings (23). To improve the accuracy of inspiratory effort estimates, transdiaphragmatic pressure (Pdi) and esophageal and transdiaphragmatic pressure-time products (PTPes, PTPdi) were measured (19, 24). Pressure and flow signals were digitized using an analog-to-digital converter system (MP100; Biopac, Santa Barbara, CA). After a stable breathing pattern was established, data were collected for 5 min under each condition.

Statistical Analysis

Results are given as mean ± SD. Two-way analysis of variance was performed to determine whether conditions influenced study variables. The significance of differences across treatments was evaluated using Fisher's test. p values of 0.05 or less were considered significant.

Patient characteristics at inclusion are reported in Table 1. The three ventilation strategies were well tolerated by all patients. A significant decrease in Vt was observed under CPAP, compared with initial/final baseline, and both PSV settings (see Table 2). Mean leakage was similar with CPAP and PSV. A slight, but significant decrease in respiratory rate was recorded during the PSV15/PEEP5 period (p < 0.05). No significant change in mean arterial pressure occurred with PSV, whereas a small increase was seen with CPAP (p < 0.05), as compared with initial baseline.

Table 3 reports arterial blood gas parameters during the study periods. PaO2/FiO2 increased significantly with 10 cm H2O PEEP (both CPAP and PSV10/PEEP10) but showed no significant change with PSV15/PEEP5, as compared with initial/final baseline. Mean PaCO2 was significantly lower under PSV15/5, as compared with CPAP (p < 0.05).

Dyspnea improved with all three ventilation strategies, and the improvement was greatest with PSV15/PEEP5 (p < 0.001; see Figure 1)

.

Figure 2

shows the individual values of the main parameters and Figure 3 depicts representative tracings in a typical patient. Table 4

TABLE 4. Respiratory drive, effort, and dynamic intrinsic positive end-expiratory pressure during the five study periods


Variable

Initial*

CPAP

PSV10/PEEP10

PSV15/PEEP5

Final
PTPes, cm H2O · s/min180 ± 101174 ± 110102 ± 57§100 ± 41§207 ± 127
PTPdi, cm H2O · s/min257 ± 144216 ± 174124 ± 103||115 ± 102||291 ± 202
WOB/min, J/min (n = 8)12.8 ± 7.28.7 ± 6.96.5 ± 3.87.7 ± 4.115.3 ± 10.0
WOB/L, J/L (n = 8)0.85 ± 0.490.70 ± 0.420.45 ± 0.19||0.44 ± 0.20||0.93 ± 0.53
PEEPi,dyn, cm H2O0.9 ± 1.00.3 ± 0.40.3 ± 0.40.5 ± 0.80.8 ± 1.1
Pdi, cm H2O11.0 ± 5.410.3 ± 7.15.8 ± 4.4§5.4 ± 4.4§12.0 ± 7.0
P0.1, cm H2O
2.7 ± 1.5
2.6 ± 1.0
1.6 ± 0.6||
± 0.6§
2.4 ± 1.4

*Initial indicates parameter value measured during the initial baseline.

p ⩽ 0.05 compared with initial baseline.

p ⩽ 0.005 compared with initial baseline.

§p ⩽ 0.005 compared with CPAP.

||p ⩽ 0.05 compared with CPAP.

Final indicates parameter value measured after the randomized sequences and return to the baseline condition.

Definition of abbreviations: CPAP = continuous positive airway pressure; P0.1 = respiratory center output estimated by the decrease in esophageal pressure developed at 100 ms, after onset of a triggered breath; Pdi = tidal transdiaphragmatic pressure-curve variations; PEEPi,dyn = dynamic intrinsic positive end-expiratory pressure; PSV = pressure-support ventilation; PTPdi = pressure-time product for the transdiaphragmatic pressure curve, per minute; PTPes = pressure-time product for the esophageal pressure curve, per minute; WOB = inspiratory work of breathing.

illustrates changes in respiratory drive, effort, and intrinsic PEEP in the overall patient population during the measurement periods. All respiratory effort parameters (WOB, PTPes, and PTPdi) were significantly lower during PSV10/PEEP10 and PSV15/PEEP5 than during initial/final baseline or CPAP. No differences were found between PSV10/PEEP10 and PSV15/PEEP5 regarding respiratory effort parameters. A slight but significant intrinsic PEEP decrease occurred with 10 cm H2O PEEP (with both CPAP and PSV10/10). Respiratory drive (P0.1) was decreased with PSV as compared with CPAP and initial/final baseline.

To our knowledge, this is the first study evaluating the effects of various NIV settings on respiratory mechanics and arterial blood gases in patients with ALI. The main results of this study can be summarized as follows: (1) both PSV settings reduced neuromuscular drive, unloaded the inspiratory muscles, and improved dyspnea; (2) when used alone in this setting, CPAP was unable to reduce inspiratory effort; (3) a PEEP level of 10 cm H2O improved oxygenation compared with initial/final baseline and with PEEP 5 cm H2O; and (4) the greatest improvement in dyspnea was obtained with the highest level of PSV.

Effects of CPAP

The inspiratory effort expended by patients with acute respiratory failure is approximately four to six times the normal value and can be brought down near the normal range by careful selection of ventilator settings (25). Noninvasive CPAP, which is the simplest form of ventilatory support, raises intrathoracic pressure, decreases arteriovenous shunting, improves oxygenation and dyspnea (8, 26), and lessens WOB in patients with cardiogenic pulmonary edema (27). Katz and Marks (8) found that CPAP used alone reduced the transpulmonary WOB in intubated patients, indicating an improvement in respiratory mechanics. Our finding that noninvasive CPAP had a minimal effect on respiratory effort, as compared with marked variations under PSV, is at variance with results from studies of cardiogenic pulmonary edema and from clinical studies showing beneficial effects in a variety of other conditions (9, 2830). Scant data are available on the comparative respiratory effects of NIV with PSV versus CPAP in nonintubated patients. A clinical trial (31) and a physiologic study in patients with cardiogenic pulmonary edema (32), together with additional physiologic studies in patients ventilated by endotracheal intubation (33), suggested that PSV might be superior over CPAP alone in terms of the clinical response and/or decrease in respiratory effort. A recent prospective randomized study evaluated whether noninvasive CPAP, compared with conventional medical treatment and oxygen alone, produced physiologic benefits and reduced the need for endotracheal intubation in patients with ALI (12). Despite a favorable early physiologic response to CPAP in terms of comfort and oxygenation, no benefits in terms of outcome variables were found. This failure of noninvasive CPAP to provide clinical benefits may be ascribable to absence of an effect on respiratory effort, as demonstrated in this study. We cannot exclude, however, that the disappointing results observed with CPAP in this study are specific to our experimental setting. It may in part be explained by the type of patient, the interface, and the ventilator used to deliver CPAP. According to the observed variations in Paw in some patients such as Patient 10 (see Figure 3), one could consider that CPAP was not fairly administered by the ventilator. Although we think that this merely reflects the high respiratory drive of the patient, this may have biased comparisons between the NIV sequences. Whether a different system or type of administration would give different results may warrant further investigation. Last, our results do not rule out potential clinical indications for CPAP. For instance, in the postoperative period, loss in lung volume and oxygenation impairment may be the main pathophysiologic pathways of respiratory complications, and CPAP may be useful in this settings (34).

A decrease in Vt occurred only with CPAP. Despite painstaking precautions, leaks occurred during the experimental procedure. Leakage was similar (≅ 35%) during all ventilation periods, and leakage alone could not explain the Vt difference seen with CPAP (Table 2). The reason for this difference is hypothetical and may be ascribable to two different phenomena. A low level of PSV was applied during the initial and final periods to compensate for the dead space imposed by the circuit and the measurement apparatus (22), thus avoiding an overestimation of patient's effort during baselines due to the measuring equipment. This low PSV level was determined on a case-by-case basis as the level providing esophageal and/or transdiaphragmatic pressure swings of identical or slightly smaller magnitude than during spontaneous breathing with no facial mask or equipment. No PSV level was added during CPAP, because this is not what is routinely performed in the intensive care unit setting. Although designed to compensate for the load imposed by the circuit during spontaneous breathing, one cannot exclude that the presence of a low PSV level during the initial and final conditions and not during CPAP could explain part of the Vt decrease noted after switching from initial baseline to CPAP. From a different prospective, CPAP has been shown to increase expiratory muscle recruitment, an effect that may contribute to reduce Vt, by worsening mechanical conditions (30, 35). Indeed, tonic expiratory muscle recruitment may tend to limit tidal excursion and Vt by decreasing chest wall and respiratory system compliance. However, this has been observed in conditions where CPAP tended to increase lung volume above normal FRC, and it is unknown whether this can also occur in the studied patients.

Effects of PSV

The changes in respiratory muscle effort observed during NIV with PSV are in accordance with previous data obtained in intubated patients (33, 36) and with clinical studies suggesting that, in selected patients with ALI, NIV may reduce the need for intubation and improve outcomes (1317, 37). In aggregate, these results suggest that adding PSV to PEEP may be indispensable in patients with ALI treated with NIV.

The main goals of NIV in patients with parenchymal lung disease such as ALI are to improve oxygenation, to unload the respiratory muscles, and to relieve dyspnea. The first goal can usually be achieved by using PEEP to recruit and stabilize previously collapsed lung tissue. A significant PaO2/FiO2 increase was observed in our study during both periods with 10 cm H2O of PEEP (CPAP and PSV10/PEEP10) but not significantly during the period with 5 cm H2O of PEEP (PSV15/PEEP5), compared with the initial and final conditions. These results suggest that the effects of NIV on oxygenation require the use of sufficient PEEP. However, in the study by Delclaux and colleagues (12), an improvement in PaO2/FiO2 in the patients given CPAP was noted only during the first few hours. Leakage and poor tolerance by the patient usually limit the end-inspiratory peak pressure during NIV. Increasing the PEEP level tends to reduce the driving pressure for Vt if the peak pressure is kept constant to limit leakage. These results suggest that clinicians must seek the best compromise, at a given end-inspiratory pressure, between increasing the PEEP level to improve oxygenation, on the one hand, and increasing the PSV level above PEEP to relieve dyspnea and diminish respiratory muscle effort on the other.

The sensation of dyspnea is influenced by several factors. In addition to the effects of hypoxemia, a major factor is excessive loading of the inspiratory muscles (38). Improved oxygenation probably explained the small but significant improvement in dyspnea observed with CPAP. The inspiratory muscles unloading provided by PSV may therefore explain why dyspnea relief was significantly better than with CPAP used alone. These results also emphasize that improving oxygenation, as with CPAP used alone, should not be the sole objective, because it is not always associated with a decrease in respiratory effort.

Study Limitations

The present study was designed to determine the physiologic short-term effects of various NIV settings, and did not seek to assess their impact on outcome. The findings, however, provide a convincing physiologic explanation to the results of some clinical trials.

Regarding physiologic measurements, a number of issues need to be briefly discussed. One limitation of the study is that neither the patients nor the investigators were blinded to the ventilator settings. This may have biased the patients' assessment of their dyspnea, although this was likely minimized by the fact that study periods were performed in random order. Major leakage occurred around the masks despite careful monitoring. However, substantial physiologic measurements were based on expiratory Vt after at least 10 min of stable breathing and signal acquisition, thus avoiding overestimation of the real volume delivered to the patient and replicating the true conditions of NIV use in acute settings.

We did not try to control for PaCO2 levels. Chemical feedback (i.e., PaCO2 values) is, however, an important determinant of respiratory motor output (3941). In a clinical study of patients with acute respiratory distress syndrome receiving PSV, the respiratory drive was shown not to be affected by short-duration ventilatory support variations (42). However, if the changes in PSV were applied for a longer period, respiratory drive and the PTP were affected, which was presumed by the authors as mediated by chemical stimuli. One may consider that in spontaneously breathing patients with ALI, such as ours, the effect of ventilatory settings on chemical feedback plays a role in their impact on respiratory muscle activity. We cannot exclude that PaCO2 changes induced by PSV in our patients influenced respiratory muscle output. Actually, these PaCO2 variations were only significant for the highest PSV level (PSV15/PEEP5).

An assessment of respiratory variables was not available per se during fully unassisted spontaneous breathing periods. The available references were the initial and final periods, where the patients were breathing with a facemask attached to a pneumotachograph and a circuit. The main issue of the measurement apparatus is generated by the facemask itself (dead space) and the connected circuits (resistances). Facemask and circuits are part of the treatment in all conditions but spontaneous breathing. During the sole spontaneous breathing periods, we thus applied a low, individually titrated 3– to 5–cm H2O pressure support level to reproduce the same Pdi swings than those observed without the facemask and with all measurement apparatuses in place. Without this setting, we could have considerably overestimated baseline efforts by measuring the effect of the mask and measurement apparatus on breathing effort. During CPAP or pressure support above PEEP, the effect of the equipment was not compensated for.

In summary, the results of the present study provide new physiologic guidance for selecting NIV settings in patients with ALI. These findings are of clinical relevance because they show that, in such patients, CPAP used alone essentially provides satisfactory gas exchange. PSV above PEEP, as compared with CPAP, provides a better physiologic response in terms of muscle unloading and dyspnea relief. Our data, together with the results of previous clinical studies, strongly support the combined use of PSV and PEEP in this situation. They also illustrate the difficulty to find the best NIV setting to reduce dyspnea, unload respiratory muscles, and increase oxygenation with a single PSV/PEEP combination.

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Correspondence and requests for reprints should be addressed to Erwan L'Her, M.D., Ph.D., Réanimation Médicale, CHU de la Cavale Blanche, 29609 Brest Cedex, France. E-mail:

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American Journal of Respiratory and Critical Care Medicine
172
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