Functional residual capacity change (ΔFRC) was assessed as follows: after a (brief 1 s) end-inspiratory occlusion, the patient was temporarily disconnected from the ventilator and allowed to exhale to respiratory system relaxation volume (15,17). ΔFRC was then computed as expired-to-tidal volume difference. After analog-to-digital conversion (sample rate = 200 Hz), respiratory mechanics data were analyzed, as previously described (15). At each study time point, respiratory mechanics were assessed in triplicate, and only mean values of the measurement sets were analyzed.
Maximal (Rmax,rs), ohmic (Rmin,rs), and additional (ΔR,rs) rs resistances were computed as corresponding Pmax – P2, Pmax – P1, and P1 – P2 differences divided by the preceding airflow. Static rs elastance (Estat,rs) was computed as P2 – PEEPi or P2 – PEEPtot (whenever PEEPe was applied), with the difference divided by the preceding tidal volume.
Heart rate, MAP, and MPAP were recorded (and averaged) over a 3-min period. Immediately thereafter, pulmonary capillary wedge pressure (PCWP) and CVP were measured at end expiration and averaged over three consecutive respiratory cycles. Subsequently, thermodilution cardiac output (CO) was determined in triplicate; injections of 10 mL of cold saline were performed during expiration. At all study time points, the variance of individual CO measurements was always <10%; thus, CO measurement repetition was never necessary (11). After CO determination, mixed venous and arterial blood gas samples were simultaneously collected and immediately analyzed. Only blood gas analysis-derived mixed venous oxygen saturation (SvO2) values were included in the subsequent data analysis (15). Systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), oxygen delivery (DO2), oxygen consumption, and shunt fraction (Qs/Qt) were calculated according to standard formulas (see Appendix).
For each of the above-mentioned time points, only the means of obtained variable value sets were analyzed. Variable comparisons among measurement time points were performed with repeated measures analysis of variance. The Scheffé test was used for post hoc analysis. Significance was set at P < 0.05. Values are presented as mean ± sd.
Complete measurement sets were obtained from all patients; no protocol-related complications (15) occurred. Nine patients were weaned from mechanical ventilation and discharged from the intensive care unit within 8–13 days postadmission, and one patient died of sepsis 11 days postadmission.
Tables 2 and 3 display results on respiratory mechanics and hemodynamics, respectively.
Relative to baseline (ZEEPe time points), the ZEEPe-S maneuver produced decreases in Rmax,rs, Rmin,rs, ΔR,rs, ΔFRC, PEEPi, PCWP, and SVR and increases in heart rate, SvO2, and DO2.
Compared to ZEEPe, the PEEPe maneuver (a) attenuated PEEPi, (b) improved Pao2, and (c) reduced Paco2 and Qs/Qt.
Relative to ZEEPe, the PEEPe-S combination caused: (a) Rmax,rs, Rmin,rs, ΔFRC, PCWP, and SVR to decrease and heart rate and DO2 to increase, similar to that observed at ZEEP-S; (b) Pao2 to increase and Qs/Qt to decrease, similar to that observed at PEEPe; (c) Estat,rs to decrease; and (d) the largest PEEPi attenuation among study time points. Figure 2 displays individual PEEPi values and shows that in four patients, PEEPi was almost completely abolished.
The major original findings of the present study are that in mechanically ventilated, bronchodilator-responsive COPD patients who exhibit a moderate PEEPi (5–10 cm H2O), the use of nebulized salbutamol and PEEPe equal to PEEPi at ZEEP results in (a) benefits with respect to inspiratory resistance, lung volume, hemodynamics, and oxygenation, (b) an additive effect with respect to PEEPi reduction, and (c) Estat,rs decrease.
Two studies (9,10) that accurately assessed inhaled drug mass proved that nebulizers deliver large amounts to the alveoli. Accordingly, we provided bronchodilation with nebulized salbutamol. The observed Rmin,rs reduction and dynamic hyperinflation attenuation are in accordance with previously published results (5,14,18–20). The observed ΔR,rs reduction is in accordance with the results of Guérin et al. (21) and is probably related to a significant, nebulizer-induced alveolar deposition of salbutamol (21).
In addition to the aforementioned results, salbutamol resulted in a CO-arithmetical increase and PVR-arithmetical decrease (Table 3). In vitro β2-adrenoceptor stimulation similarly increased heart rate and reduced SVR but also reduced MAP without affecting CO (22). In ambulatory, stable COPD patients at rest and breathing room air, inhaled β2 agonists similarly increased heart rate and CO but decreased PVR significantly (23). However, the present study’s participants continuously received 0.35–0.50 Fio2, with some probable blunting of hypoxic pulmonary vasoconstriction and PVR decrease, even at baseline ventilation.
In ambulatory, stable COPD patients, β2-adrenergic agonists induced pulmonary artery vasodilation and attenuated hypoxic pulmonary vasoconstriction (23). This, in conjunction with CO increase, caused preferential pulmonary blood flow deviation to poorly ventilated lung regions. Consequently, right-to-left shunt increased and oxygenation deteriorated (23). However, DO2 was well-preserved because of CO increase (23). In general, such effects were not observed in our study. The preservation of arterial oxygenation may be attributable to the salbutamol-induced reduction in ΔR,rs, which reflects reduced lung time-constant inequality and more homogenous ventilation distribution. A previous study (5) also evaluated bronchodilation effects on Pao2 in mechanically ventilated COPD patients; the observed Pao2 changes were insignificant.
PEEPe Application Effects
In COPD, applying PEEPe at the PEEPi level determined at ZEEPe may increase PEEPtot, accentuate dynamic hyperinflation, and compromise hemodynamics and gas exchange (11,12). Consequently, such a maneuver cannot be generally recommended. However, in our carefully preselected COPD group, the application of PEEPe equal to PEEPi at ZEEPe resulted mainly in favorable effects with respect to gas exchange and PEEPi. Our results are in accordance with those of Guérin et al. (7), who found that PEEPe application close to PEEPi reduces the inspiratory breathing work without further promoting hyperinflation.
Lung hyperinflation compresses the intraalveolar vessels, exacerbates any preexisting tricuspid incompetence, and increases right ventricular afterload (12). Hypovolemia reduces right and left ventricular preload and alveolar vessel volume, thus further deteriorating hemodynamics. In this setting, PEEPe application decreases MAP (12) and increases intrathoracic pressure with further preload compromise.
In the present study, the PEEPe level we used did not produce any significant changes in lung volume or hemodynamics. Before entering the study, all patients underwent transthoracic echocardiography, were evidently normovolemic, and had good right ventricular function. Neither tricuspid regurgitation nor severe pulmonary hypertension was present. Furthermore, PEEPe probably recruited unaerated or poorly ventilated alveoli, thus causing a more homogenous ventilation distribution. Because CO did not change significantly, we speculated that pulmonary blood flow passed through lung regions that were better aerated overall. Thus, ventilation-perfusion mismatch was attenuated, and gas exchange was improved.
In contrast to our results (Table 3), Tuxen (2) reported that PEEPe application decreased MAP and DO2 in mechanically ventilated asthmatics. The differences between the two studies lie in the pathophysiologic profiles of asthmatics and COPD patients. In asthmatics, airway wall progressive stiffness (caused by increased bronchial tone and inflammatory infiltration) does not result in complete airway collapse, even when airway caliber is reduced (2). However, COPD patients exhibit increased airway collapsibility secondary to progressive elastic recoil loss. Moreover, Tuxen (2) administered larger baseline tidal volumes (15 ± 3 mL/kg) that could have exacerbated hyperinflation. The studies of Rossi et al. (6), Ranieri et al. (11), and Dambrosio et al. (13) suggest that PEEPe should not exceed a critical value of 50%–91% of PEEPi, more than which ΔFRC and Estat,rs increase and CO decreases. However, analysis of the data of the aforementioned studies shows that (a) baseline PEEPi values amounted to 9.45 ± 1.99, 9.8 ± 0.5, and 9.7 ± 0.4 cm H2O, respectively; (b) PEEPe equal to PEEPi at ZEEPe appreciably reduced PEEPi; and (c) the rest of rs mechanics and hemodynamics remained unaffected up to PEEPtot of 10.23 ± 2.41, 11.1 ± 0.3, and 10.93 ± 0.85 cm H2O, respectively. Our patients exhibited lower baseline PEEPi values (7.0 ± 1.1 cm H2O), whereas inspiratory resistance, hyperinflation, and hemodynamics did not change significantly up to PEEPtot values of 10.8 ± 2.2 cm H2O. In accordance with our results, Rossi et al. (6) showed that PEEPe resulting in PEEPtot of 10.23 ± 2.41 cm H2O substantially improved arterial oxygenation with concomitant Paco2 decrease; this was also attributed to perfusion redistribution to more efficient alveoli.
PEEPe and Nebulized Salbutamol Combination Effects
In the particular setting of the present study, the PEEPe/salbutamol combination resulted in additive favorable effects on most determined variables and, especially, on PEEPi (Figure 2). It seems likely that PEEPe recruitment of poorly or nonventilated alveoli resulted in distribution of inspired gas (and consequently of nebulized salbutamol particles) to a larger portion of the lung parenchyma. Furthermore, the salbutamol-induced reduction in lung time-constant inequality (i.e., ΔR,rs) (Table 2) and more homogenous ventilation distribution could have facilitated the intratidal alveolar recruitment, whereas the applied PEEPe should have facilitated the maintenance of such recruitment. Thus, PEEPe alveolar recruitment was followed by the salbutamol-induced (arithmetical) CO increase, and salbutamol-facilitated PEEPe alveolar recruitment. This interpretation is supported by the low Qs/Qt and improved arterial oxygenation, which suggest improved ventilation-perfusion relationships. The significant reduction in Estat,rs relative to ZEEPe is consistent with the PEEPe-induced reduction in alveolar atelectasis (15) and the concomitant bronchodilation-induced attenuation of lung hyperinflation.
Critique on Methods
The responses to salbutamol might have been limited by corticosteroid-induced bronchodilation (20). Also, single 0.8-mg/kg methylprednisolone-bolus administration (not preceded by steroid treatment) may acutely decrease Rmin,rs and dynamic hyperinflation (24). However, a previous randomized, controlled trial (25) demonstrated that the beneficial effects of intermittent IV methylprednisolone on forced expiratory lung volumes are maximized within 48 h of treatment initiation and are maintained virtually constant thereafter. Because the present study’s participants were enrolled at least 48 h after IV steroid initiation (see Methods), it is unlikely that such treatment has qualitatively influenced our results (20).
A randomized crossover study design might have been more appropriate because a patient’s clinical condition could have changed over the 11-hour study period. If study sequence is always the same, it may be impossible to identify residual effects of inhaled salbutamol on PEEPe application or PEEPe-S, despite allowing an eight-hour washout period. These concepts probably do not apply here because (a) Tables 2 and 3 confirm that before PEEPe application, all determined variable values had returned to ZEEPe levels, (b) individual response patterns to salbutamol washout were similar (data not shown), (c) no significant clinical events/deterioration (e.g., hypoxemia or hemodynamic instability) occurred throughout the study period in any case; such events would have caused patient exclusion (see Methods), and complete measurement sets would have not been obtained in all cases (see Results); and (d) in most cases, substantial clinical improvement allowing weaning from mechanical ventilation occurred 5–10 days after study enrollment; consequently, the 11-hour study period should have been too short for a study result affecting clinical change.
Clinical Implications and Further Research
In COPD, PEEPi is not evenly distributed throughout the lung parenchyma. EEO-measured, average PEEPi of 10 cm H2O may correspond to a wide regional PEEPi variation. Maximal PEEPi values (which are probably substantially higher than the EEO-measured average) are encountered by alveoli that are cut off from the airway opening. However, lung regions with the highest PEEPi values may be especially prone to barotrauma. According to our results, combined bronchodilation/PEEPe minimizes PEEPi in an additive manner. Consequently, such treatment may be recommendable for mechanically ventilated COPD patients who are bronchodilator responsive and exhibit a moderate PEEPi of 5–10 cm H2O.
It could be argued that because at PEEPe-S the inhaled salbutamol further decreased PEEPi, the setting of PEEPe at a PEEPi level determined at ZEEPe might result in a PEEPe exceeding average effective PEEPi, with consequent accentuation of dynamic hyperinflation. This is supported by the substantial arithmetical ΔFRC difference between ZEEPe-S and PEEPe-S reported in Table 2. Thus, one could advocate PEEPe counterbalancing of the PEEPi present at ZEEPe-S (and not at ZEEPe). However, it should be noted that the PEEPi value present at ZEEP-S returned to baseline (i.e., PEEPi value at ZEEPe) approximately eight hours after inhaled salbutamol (Table 2). Consequently, an ideal PEEPe strategy could comprise intermittent (e.g., every one to two hours) determination of PEEPi after inhaled salbutamol, with concomitant “appropriate” adjustment of PEEPe.
If our results were applicable during partial ventilatory support, then combined bronchodilation/PEEPe could result in substantial unloading of inspiratory muscles by minimizing PEEPi (1,3). This would probably facilitate the weaning process. Consequently, the above speculations warrant further investigation.
In bronchodilator-responsive COPD patients exhibiting moderate PEEPi, combined PEEPe-counterbalancing of PEEPi, and nebulized salbutamol minimize PEEPi, attenuate lung hyperinflation and inspiratory resistance, and exhibit a favorable hemodynamic and gas exchange profile.
Appendix: Formulas Used to Derive Predicted Body Weight and Hemodynamic* and Gas Exchange Variables**
1. Predicted body weight (males) = 50 + (height [cm] – 152.4) × 0.91
2. Predicted body weight (females) = 45.5 + (height [cm] – 152.4) × 0.91
3. SVR = (MAP – CVP) × 80
4. PVR = (MPAP – PCWP) × 80
5. O2 delivery2 = CO × 1.36 × Hgb × Sao2
6. O2 consumption = CO × 1.36 × Hgb × (Sao2 – Svo2)
7. Respiratory quotient = (FEY of carbohydrate intake) × 1.0 + (FEY of protein intake) × 0.8 + (FEY of lipid intake) × 0.7**
8. Alveolar Po2 = Pio2 – Paco2 × (Fio2 – [1 – Fio2] × R−1); Pio2 = Fio2 × (PB – 47); Paco2 ∼ Paco2
9. O2 content of blood = Hgb × 1.36 × So2/10 + 0.003 × Po2
10. Shunt fraction = (CcO2 – CaO2)/(CcO2 – CvO2)
CO = cardiac output (L/min); MAP = mean arterial blood pressure (mm Hg); CVP = central venous pressure (mm Hg); 80 = transformation factor of Wood units (mm Hg·L−1·min−1) to standard metric units (dynes·s−1·cm−5); MPAP = mean pulmonary artery pressure (mm Hg); PCWP, = pulmonary capillary wedge pressure (mm Hg); Hgb = hemoglobin concentration in g/L; 1.36 = O2 combining power of 1 g of Hgb (mL); Sao2 = arterial O2 saturation determined by the blood gas analysis reported in Methods; Svo2 = mixed venous O2 saturation; FEY = fractional energy yield relative to the total of prescribed nutritional support; P = gas partial pressure (mm Hg); Pio2 = inspired O2 partial pressure (mm Hg); Paco2 = alveolar CO2 partial pressure (mm Hg); Fio2 = fraction of inspired O2; R = respiratory quotient; PB = barometric pressure (mm Hg); 47 = water saturated vapor pressure at 37°C (mm Hg); 0.003 = O2 solubility coefficient at 37°C (mL·dL−1·mm Hg−1); Po2 = O2 partial pressure (mm Hg); CcO2/CaO2/CvO2 = O2 content in end-capillary/arterial/mixed-venous blood, respectively.
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