Increases in ventilation in the dorsal region and decreases in ventral ventilation were significantly larger with PEEP 7 cm H2O than with PEEP 5 cm H2O and with FLEX than without FLEX at both PEEP levels (Figure 5).
We observed no critical incidents or FLEX malfunctions in any measurement that would have required an intervention or termination of the measurement.
When FLEX was applied to patients undergoing neurosurgery, expected effects were easily observable in respiratory measurement parameters and ventilation curves, especially the early peak expiratory flow. FLEX increased ventilation in the dorsal-dependent lung regions, thereby homogenizing the ventilation distribution. At the same time, FLEX did not affect hemodynamics or oxygenation. The principal findings of the study indicate that FLEX improves the distribution of inspired ventilation as a consequence of more uniform homogeneous lung emptying during expiration and can be used in adult patients under controlled mechanical ventilation during general anesthesia.
FLEX decreased early expiratory peak flow and FLEX increased late expiratory flow. In contrast, during conventional expiration lung emptying is rapid with a sudden pressure drop. As a consequence, FLEX increased mean airway pressure by 1 cm H2O. By contrast, increasing PEEP from 5 to 7 cm H2O shifted all pressure levels and thus mean airway pressure by the amount of the PEEP increase, that is, by 2 cm H2O.
Analysis of regional ventilation revealed in our patients in supine position, a typical shift from ventral (nondependent) to dorsal (dependent) regions of the lungs with PEEP 7 cm H2O compared with 5 cm H2O.12 Similarly, FLEX shifted ventilation from ventral to dorsal regions, improving overall regional ventilation in the same fashion as an increased PEEP but without increasing peak and plateau airway pressures.
FLEX is a relatively new procedure, and to date, no published studies in humans exist. We also did not evaluate pulmonary hemodynamics or cardiac output in our study because the invasiveness of such measurements was not justifiable for such an experimental device. However, in our study, we found no FLEX-dependent effects on heart rate, mean arterial blood pressure, or catecholamine demand. In our study, in pigs with artificial lung injury, we also found no adverse effects of FLEX on heart rate, mean arterial pressure, central venous pressure, the cardiac index, or resistance in the systemic circulatory system.6 Under FLEX, only the mean pulmonary blood pressure and the pulmonary capillary wedge pressure were decreased. In another initial study with FLEX13 in healthy conscious volunteers, we also observed no hemodynamic effects. The current study supports our hypothesis that FLEX is hemodynamically neutral.
In lung-injured pigs, FLEX was associated with several lung protective effects: after 6 hours of mechanical ventilation, decarbonization was improved and various markers of ventilation-induced lung injury were lower with FLEX compared with conventional ventilation. Furthermore, to reach a comparable Pao2 at the same Fio2, 20% lower PEEP was required with FLEX than without.6 Although the mechanism for this PEEP effect is unclear, one possibility is that FLEX may stabilize dependent areas of the lung previously recruited by plateau pressure and prevented from derecruitment during expiration. Potential positive effects of FLEX such as improved gas exchange with limited effect on hemodynamics may then be a consequence. However, in the current study with lung-healthy patients, we found no significant effects of FLEX or PEEP on gas exchange. Further studies are required to investigate the potentially beneficial effects in patients with less favorable preconditions.
It is a paradigm of nearly all mechanical ventilation modes that expiration is passive and therefore governed by the mechanical characteristics of the respiratory system. Thus, in patients with stiff lungs (ie, low compliance), expiration is relatively rapid compared with that in patients with high compliance like in chronic obstructive pulmonary disease. Furthermore, because expiration is not normally managed by the attending physician, expiratory time is not normally considered a target for potential therapy. In patients with restrictive lung injury, expiratory peak flow rates during passive expiration are often very high, and lung emptying proceeds within a few hundred milliseconds.14 This rapid lung emptying means that fast and slow compartments empty in an inhomogeneous fashion that probably increases shear stress in the lung parenchyma. Such patients may benefit from a more homogenous lung emptying as a result of controlled expiration.
In patients with obstructive lung diseases, flow limitation and air trapping result from caliber reductions of small airways in response to high local flow rates.15 These patients are often trained to exhale against pursed lips to increase airway pressure during expiration. In the unconscious patient with furthermore intubated/bridged airways, this breathing technique is not applicable. During mechanical ventilation, FLEX may be a mechanical surrogate for pursed lip breathing by “externally” reducing expiratory flow rate and increasing airway pressure during expiration. However, because we excluded these patient groups from our study, the potential effects need to be investigated in appropriate trials.
Earlier approaches have also aimed at decelerating expiration by adding a constant expiratory resistance.16,17 Although the ideas behind these approaches are similar to that of FLEX, the constant expiratory resistance increases expiratory time. Incomplete expiration might therefore have prevented clinically relevant benefits17,18 In contrast, FLEX does not prolong expiration time to a large extent. With FLEX, the expiratory flow is limited in the early expiration. As a consequence, the lung volume empties in a decelerated fashion and an expiratory gas flow is achieved nearly throughout expiration. During late expiration, however, the pressure in the lung decreases to a level at which the “targeted” flow rate cannot be achieved any more and the flow rate drops to 0. Dynamic hyperinflation may thus be detected by expiratory gas flow at the end of expiration immediately before the subsequent inspiration begins.
Our patient population and sample size do not allow us to evaluate lung-protective effects of FLEX. Longer intervention times may also be needed to show detectable differences in the application of FLEX with respect to an improvement in oxygenation.
This study is the first step in the evaluation of FLEX in patients under controlled ventilation. Our findings suggest potential benefits for different patient groups (eg, chronic obstructive pulmonary disease, acute respiratory distress syndrome, increased intra-abdominal pressure). Our principle-of-proof study was not designed to investigate outcome variables, and in our patients, effects of FLEX were limited on the homogenized ventilation. However, the homogenizing effects of FLEX may be considered lung protective. Because no adverse effects on hemodynamics were observed, FLEX may be another ventilatory option for lung-protective ventilation.
With our proof-of-principle study, we could not investigate all aspects of controlled expiration. FLEX offers various modalities. FLEX may be applied only to reduce the initial expiratory peak flow or to maintain a linearized flow throughout the full expiration phase. Furthermore, other than linear expiratory flow profiles, for example, sine-shaped, may be applied. Further studies are needed to clarify the effects of FLEX on other ventilator parameters.
In our pilot study of 34 patients, FLEX increased mean airway pressure moderately. Comparable to an increase of PEEP, FLEX improved the ventilation in the dorsal areas and thus homogenized regional ventilation, however, without changing PEEP and peak pressure. We found no adverse effects of FLEX on hemodynamic parameters. Patients with impaired lung function of various origins may potentially benefit from ventilation with FLEX.
The authors thank Dr Gerta Rücker from the Institute for Medical Biometry and Statistics of the University of Freiburg for her profound advice on the statistical analyses.
Name: Steffen Wirth, MD.
Contribution: This author helped conceptualize and design the study, organize the study, analyze and interpret the data, and write the manuscript.
Name: Sebastian Springer, MD.
Contribution: This author helped conduct the study, acquire and analyze and interpret the data, and write the manuscript.
Name: Johannes Spaeth, MD.
Contribution: This author helped analyze the data and write the manuscript.
Name: Silke Borgmann, PhD.
Contribution: This author helped analyze the data (EIT) and write the manuscript.
Name: Ulrich Goebel, MD.
Contribution: This author helped recruit subjects, acquire the data, and write the manuscript.
Name: Stefan Schumann, PhD.
Contribution: This author helped conceptualize and design the study, interpret the data, and write the manuscript.
This manuscript was handled by: Avery Tung, MD, FCCM.
1. Tusman G, Böhm SH, Warner DO, Sprung J. Atelectasis and perioperative pulmonary complications in high-risk patients. Curr Opin Anaesthesiol. 2012;25:1–10.
2. Severgnini P, Selmo G, Lanza C, et al. Protective mechanical ventilation during general anesthesia for open abdominal surgery improves postoperative pulmonary function. Anesthesiology. 2013;118:1307–1321.
3. Hemmes SN, Gama de Abreu M, Pelosi P, Schultz MJ. High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet. 2014;384:495–503.
4. Futier E, Constantin JM, Paugam-Burtz C, et al.; IMPROVE Study GroupA trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med. 2013;369:428–437.
5. Schumann S, Goebel U, Haberstroh J, et al. Determination of respiratory system mechanics during inspiration and expiration by FLow-controlled EXpiration (FLEX): a pilot study in anesthetized pigs. Minerva Anestesiol. 2014;80:19–28.
6. Goebel U, Haberstroh J, Foerster K, et al. Flow-controlled expiration: a novel ventilation mode to attenuate experimental porcine lung injury. Br J Anaesth. 2014;113:474–483.
7. Guttmann J, Eberhard L, Fabry B, Bertschmann W, Wolff G. Continuous calculation of intratracheal pressure in tracheally intubated patients. Anesthesiology. 1993;79:503–513.
8. Zhao Z, Steinmann D, Frerichs I, Guttmann J, Möller K. PEEP titration guided by ventilation homogeneity: a feasibility study using electrical impedance tomography. Crit Care. 2010;14:R8.
9. Lindberg P, Gunnarsson L, Tokics L, et al. Atelectasis and lung function in the postoperative period. Acta Anaesthesiol Scand. 1992;36:546–553.
10. Luepschen H, Meier T, Grossherr M, Leibecke T, Karsten J, Leonhardt S. Protective ventilation using electrical impedance tomography. Physiol Meas. 2007;28:S247–S260.
11. Rothen HU, Sporre B, Engberg G, Wegenius G, Reber A, Hedenstierna G. Atelectasis and pulmonary shunting during induction of general anaesthesia—can they be avoided? Acta Anaesthesiol Scand. 1996;40:524–529.
12. Wirth S, Kreysing M, Spaeth J, Schumann S. Intraoperative compliance profiles and regional lung ventilation improve with increasing positive end-expiratory pressure. Acta Anaesthesiol Scand. 2016;60:1241–1250.
13. Wirth S, Best C, Spaeth J, Guttmann J, Schumann S. Flow controlled expiration is perceived as less uncomfortable than positive end expiratory pressure. Respir Physiol Neurobiol. 2014;202:59–63.
14. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med. 2006;32:24–33.
15. Pinhu L, Whitehead T, Evans T, Griffiths M. Ventilator-associated lung injury. Lancet. 2003;361:332–340.
16. Aerts JG, van den Berg B, Bogaard JM. Controlled expiration in mechanically-ventilated patients with chronic obstructive pulmonary disease (COPD). Eur Respir J. 1997;10:550–556.
17. Georgopoulos D, Mitrouska I, Markopoulou K, Patakas D, Anthonisen NR. Effects of breathing patterns on mechanically ventilated patients with chronic obstructive pulmonary disease and dynamic hyperinflation. Intensive Care Med. 1995;21:880–886.
18. Gültuna I, Huygen PE, Ince C, Strijdhorst H, Bogaard JM, Bruining HA. Clinical evaluation of diminished early expiratory flow (DEEF) ventilation in mechanically ventilated COPD patients. Intensive Care Med. 1996;22:539–545.
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