Attempts at maintaining gas exchange during acute and chronic failure of the respiratory system can be traced back to the mid-16th century [1]. Routine clinical use of supportive mechanical ventilation began in the early 20th century with so-called “iron lungs,” devices in which patients could be encased into a cycling negative pressure field, mimicking the function of the respiratory musculature. The transition to positive pressure ventilation began during the polio epidemic of the 1950s, given the substantial improvement in mortality in comparison to negative pressure ventilation [2]. As a result, positive pressure ventilators became indispensable medical devices for sustaining patients in intensive care units, operating rooms, and long-term treatment facilities. The subsequent rapid evolution of mechanical ventilators in the second half of the 20th century would not have been possible without the tireless efforts of clinicians, physiologists, and most notably, engineers. The modern mechanical ventilator is now a highly sophisticated, yet elegant medical device with a myriad of modalities and functions to meet the complex demands of a failing respiratory system. But despite best intentions, these ventilators at times may unintentionally do more harm than good to the patients they serve.

At the most basic level, the parameters most often adjusted on a ventilator include the amount of gas delivered with each breath (the tidal volume), the rate at which this gas is cyclically applied (the frequency), and the level of pressure applied to the airway at end-expiration (positive end-expiratory pressure, or PEEP). However, improper setting of these parameters can result in a secondary, “ventilator-induced lung injury” (VILI) that can worsen existing lung pathology. This is particularly true for one of the most common, and deadly, presentations of acute respiratory failure, termed the “acute respiratory distress syndrome,” or ARDS—a very complex pathologic process with heterogeneous interactions of mechanical and biochemical phenomena [3]. ARDS is characterized by hypoxic respiratory failure in the presence of widespread inflammation, edema, and derecruitment of airspaces in the lung. Its pathophysiology is often conceptualized as a two-compartment model, consisting of mechanically “normal” lung tissue in one compartment, and collapsed and edematous “injured” tissue in the other. Collapsed lung tissue significantly reduces the effective surface area available for sufficient gas exchange. It is postulated that the primary mechanisms for VILI in ARDS are: (1) overdistension of the normal compartment, especially when using tidal volumes that may be more appropriate for a healthy, fully recruited lung; and (2) cyclic opening and closing (i.e., recruitment and derecruitment) of the injured compartment [4]. This has led to the development of ventilation protocols designed to “protect” the normal compartment with lower tidal volumes to minimize overdistention, while “resting” the injured compartment by allowing it to be either consistently recruited or remain collapsed throughout the ventilator cycle [5]. However, this “protect and rest” strategy has not dramatically lowered mortality in patients with established ARDS [68], despite its widespread adoption in clinical practice almost 20 years ago [9].

Recent studies suggest that cyclic overdistention and recruitment/derecruitment, as exemplified by this two-compartment model, are not the only mechanisms for VILI. Lung regions with collapsed and unstable alveoli, causing excessive local points of strain and inflammation, also serve as “engines” driving progressive VILI [5,10,11]. Dynamic alveolar overdistention is certainly an important contributor to VILI, but only in tissues adjacent to alveoli already experiencing high strain, in a synergistic, “rich-get-richer” fashion [12]. Prone positioning, which is known to homogenize and reduce regional stress and strain within the lung, also limits progressive VILI in animal models of ARDS [11,13] and reduces ARDS-associated mortality [14]. These studies thus indicate that heterogeneous regional stress and strain are also important mechanisms for VILI, and if minimized, may reduce the risk of worsening lung injury. Moreover, the cyclic recruitment and derecruitment of lung tissue with each delivered tidal volume results in focal points of periodic stress within the parenchyma. Such instability of alveoli ultimately causes structural damage to the connective tissue framework of the lung [15]. Alveolar collapse also results in the loss of interdependence and tethering between adjacent alveoli, which further exacerbates tissue damage and increases the pressure necessary to re-inflate the derecruited lung.

Given these mechanisms for VILI, it becomes apparent that the durations of inspiration and expiration are critical to the opening and closing of alveoli during the process of mechanical ventilation. There is a time lag from when the pressure is applied to a derecruited lung region and when its alveoli may fully recruit, or when pressure is released and the alveoli collapse. In the injured lung with ARDS, the rates at which alveoli open or close are pathologically altered, rendering their recruitment/derecuitment dynamics dependent on both time and pressure [16]. This means that it will take a longer time at a given pressure level to open alveoli during inspiration, but a shorter time at a lower pressure before they collapse. Alveolar edema and surfactant deactivation are hallmarks of ARDS pathophysiology and are thus the main mechanisms by which the rates of alveolar opening and closing are altered. Surfactant dysfunction predisposes alveoli to collapse. Thus, without appropriate airway pressure, alveoli will progressively collapse and expand lung regions subject to excessive strain. Such collapsed alveoli require more time and pressure to re-open, further perpetuating excessive regional strain. Thus, it is not only the level of applied airway pressure, but also the duration over which such pressure is applied and released that is important for recruitment and stabilization.

Based on this understanding of alveolar recruitment/derecruitment dynamics, an engineer may ask, “Can a mechanical breath from the ventilator be designed to open and stabilize the alveoli, while still reducing the risk for VILI?” The “open lung approach”is a protective ventilation strategy that is designed to open and stabilize the lung with appropriate PEEP, while minimizing regional lung strain with reduced tidal volume. However, low tidal volume may actually worsen the distribution of gas flow and spatial strain within the lung, even with PEEP as high as 15 cmH2O, and is ineffective at preventing alveolar derecruitment [11].

Given that ARDS causes alveolar recruitment to become dependent on both time and pressure, newer ventilator modalities are actively being developed [17]. One such example is time-controlled adaptive ventilation (TCAV), which uses the airway pressure release ventilation (APRV) mode. The TCAV protocol relies on an extended duration of the inspiratory phase with a specified pressure level to recruit alveoli, and a very short expiratory duration to prevent recollapse, as compared to other protocols using APRV [17]. In the acutely injured lung, inspiratory and expiratory durations are critical for “sticky” alveoli to open, and to prevent the closure of alveoli with very short time constants of collapse [15,16,1821]. With TCAV, the inspiratory duration is extended to about 80–90% of the total respiratory cycle, which gradually “nudges” closed alveoli open each breath. However, the expiratory duration is shortened to the point that unstable alveoli do not have enough time to collapse (Fig. 1). The TCAV algorithm then adaptively adjusts the expiratory duration based on individual pathophysiology, such that the inspiratory phase is cycled when the airway flow from the patient is about 75% of the peak expiratory flow [17]. Such adaptive adjustments in inspiratory and expiratory time (to open and stabilize alveoli) is far superior for improving lung function and gas exchange, compared to the traditional practice of high PEEP with extended expiratory times [2224].

Thus to decrease the mortality associated with ARDS and other forms of acute respiratory failure necessitating mechanical ventilation, all key factors associated with VILI must be analyzed, including: (1) the maldistribution of stress and strain throughout the lung pathophysiology resulting from mechanically heterogeneity; (2) the propagation of further lung injury from inflammation and structural damage, as a direct result of such heterogeneity; and (3) the dependence of pressure and time on the opening and closing dynamics of acutely injured alveoli. Based on the knowledge of such pathophysiological phenomena and sound engineering principles, novel protective ventilation strategies that effectively open and stabilize alveoli can be designed, implemented, and even enhanced. The development of protective ventilation strategies such as TCAV is one example by which engineers can contribute their unique insight and skill set, with a fresh interpretation of the deranged mechanics of the acutely injured lung.

Acknowledgment

Dr. Kaczka is a co-founder and shareholder of OscillaVent, Inc., and a medical advisor to Monitor Mask, Inc., Mr. Nieman reports grants from Dräger Medical Systems, Inc., and presented, received travel reimbursement, and honorarium at event(s) sponsored by Dräger Medical Systems, Inc., and has lectured for Intensive Care On-line Network, Inc. (ICON).

References

References
1.
Vesalius
,
A.
,
1543
, “
De Humani Corporis Fabrica
,” School of Medicine, Padua, Italy,
epub
.https://www.erara.ch/doi/10.3931/e-rara-20094
2.
Lassen
,
H. C.
,
1953
, “
A Preliminary Report on the 1952 Epidemic of Poliomyelitis in Copenhagen With Special Reference to the Treatment of Acute Respiratory Insufficiency
,”
Lancet
,
261
(6759), pp.
37
41
.
3.
Thompson
,
B. T.
,
Chambers
,
R. C.
, and
Liu
,
K. D.
,
2017
, “
Acute Respiratory Distress Syndrome
,”
N. Engl. J. Med.
,
377
(
19
), pp.
1904
1905
.
4.
Amini
,
R.
,
Herrmann
,
J.
, and
Kaczka
,
D. W.
,
2017
, “
Intratidal Overdistention and Derecruitment in the Injured Lung: A Simulation Study
,”
IEEE Trans. Biomed. Eng.
,
64
(
3
), pp.
681
689
.
5.
Cereda
,
M.
,
Xin
,
Y.
,
Meeder
,
N.
,
Zeng
,
J.
,
Jiang
,
Y.
,
Hamedani
,
H.
,
Profka
,
H.
,
Kadlecek
,
S.
,
Clapp
,
J.
,
Deshpande
,
C. G.
,
Wu
,
J.
,
Gee
,
J. C.
,
Kavanagh
,
B. P.
, and
Rizi
,
R. R.
,
2016
, “
Visualizing the Propagation of Acute Lung Injury
,”
Anesthesiology
,
124
(
1
), pp.
121
131
.
6.
Bellani
,
G.
,
Laffey
,
J. G.
,
Pham
,
T.
,
Fan
,
E.
,
Brochard
,
L.
,
Esteban
,
A.
,
Gattinoni
,
L.
,
van Haren
,
F.
,
Larsson
,
A.
,
McAuley
,
D. F.
,
Ranieri
,
M.
,
Rubenfeld
,
G.
,
Thompson
,
B. T.
,
Wrigge
,
H.
,
Slutsky
,
A. S.
, and
Pesenti
,
A.
,
2016
, “
Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries
,”
JAMA
,
315
(
8
), pp.
788
800
.
7.
Phua
,
J.
,
Badia
,
J. R.
,
Adhikari
,
N. K. J.
,
Friedrich
,
J. O.
,
Fowler
,
R. A.
,
Singh
,
J. M.
,
Scales
,
D. C.
,
Stather
,
D. R.
,
Li
,
A.
,
Jones
,
A.
,
Gattas
,
D. J.
,
Hallett
,
D.
,
Tomlinson
,
G.
,
Stewart
,
T. E.
, and
Ferguson
,
N. D.
,
2009
, “
Has Mortality From Acute Respiratory Distress Syndrome Decreased Over Time?: A Systematic Review
,”
Am. J. Respir. Crit. Care Med.
,
179
(
3
), pp.
220
227
.
8.
Rezoagli
,
E.
,
Fumagalli
,
R.
, and
Bellani
,
G.
,
2017
, “
Definition and Epidemiology of Acute Respiratory Distress Syndrome
,”
Ann. Transl. Med.
,
5
(
14
), p.
282
.
9.
The Acute Respiratory Distress Syndrome Network
,
Brower
,
R. G.
,
Mathay
,
M. A.
,
Morris
,
A.
,
Schoenfeld
,
D.
,
Thompson
,
B. T.
, and
Wheeler
,
A.
,
2000
, “
Ventilation With Lower Tidal Volumes as Compared With Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome
,”
New Engl. J. Med.
,
342
(18), pp.
1301
1308
.
10.
Cressoni
,
M.
,
Chiurazzi
,
C.
,
Gotti
,
M.
,
Amini
,
M.
,
Brioni
,
M.
,
Algieri
,
I.
,
Cammaroto
,
A.
,
Rovati
,
C.
,
Massari
,
D.
,
di Castiglione
,
C. B.
,
Nikolla
,
K.
,
Montaruli
,
C.
,
Lazzerini
,
M.
,
Dondossola
,
D.
,
Colombo
,
A.
,
Gatti
,
S.
,
Valerio
,
V.
,
Gagliano
,
N.
,
Carlesso
,
E.
, and
Gattinoni
,
L.
,
2015
, “
Lung Inhomogeneities and Time Course of Ventilator-Induced Mechanical Injuries
,”
Anesthesiology
,
123
(
3
), pp.
618
27
.
11.
Motta-Ribeiro
,
G. C.
,
Hashimoto
,
S.
,
Winkler
,
T.
,
Baron
,
R. M.
,
Grogg
,
K.
,
Paula
,
L. F. S. C.
,
Santos
,
A.
,
Zeng
,
C.
,
Hibbert
,
K.
,
Harris
,
R. S.
,
Bajwa
,
E.
, and
Vidal Melo
,
M. F.
,
2018
, “
Deterioration of Regional Lung Strain and Inflammation During Early Lung Injury
,”
Am. J. Respir. Crit. Care Med.
,
198
(
7
), pp.
891
902
.
12.
Hamlington
,
K. L.
,
Bates
,
J. H. T.
,
Roy
,
G. S.
,
Julianelle
,
A. J.
,
Charlebois
,
C.
,
Suki
,
B.
, and
Smith
,
B. J.
,
2018
, “
Alveolar Leak Develops by a Rich-Get-Richer Process in Ventilator-Induced Lung Injury
,”
PLoS One
,
13
(
3
), p.
e0193934
.
13.
Xin
,
Y.
,
Cereda
,
M.
,
Hamedani
,
H.
,
Pourfathi
,
M.
,
Siddiqui
,
S.
,
Meeder
,
N.
,
Kadlecek
,
S.
,
Duncan
,
I.
,
Profka
,
H.
,
Rajaei
,
J.
,
Tustison
,
N. J.
,
Gee
,
J. C.
,
Kavanagh
,
B. P.
, and
Rizi
,
R. R.
,
2018
, “
Unstable Inflation Causing Injury: Insight From Prone Position and Paired CT Scans
,”
Am. J. Respir. Crit. Care Med.
,
198
(
2
), pp.
197
207
.
14.
Guerin
,
C.
,
Reignier
,
J.
,
Richard
,
J. C.
,
Beuret
,
P.
,
Gacouin
,
A.
,
Boulain
,
T.
,
Mercier
,
E.
,
Badet
,
M.
,
Mercat
,
A.
,
Baudin
,
O.
,
Clavel
,
M.
,
Chatellier
,
D.
,
Jaber
,
S.
,
Rosselli
,
S.
,
Mancebo
,
J.
,
Sirodot
,
M.
,
Hilbert
,
G.
,
Bengler
,
C.
,
Richecoeur
,
J.
,
Gainnier
,
M.
,
Bayle
,
F.
,
Bourdin
,
G.
,
Leray
,
V.
,
Girard
,
R.
,
Baboi
,
L.
,
Ayzac
,
L.
, and
PROSEVA Study Group
,
2013
, “
Prone Positioning in Severe Acute Respiratory Distress Syndrome
,”
N. Engl. J. Med.
,
368
, pp.
2159
2168
.
15.
Nieman
,
G. F.
,
Satalin
,
J.
,
Kollisch-Singule
,
M.
,
Andrews
,
P.
,
Aiash
,
H.
,
Habashi
,
N. M.
, and
Gatto
,
L. A.
,
2017
, “
Physiology in Medicine: Understanding Dynamic Alveolar Physiology to Minimize Ventilator-Induced Lung Injury
,”
J. Appl. Physiol.
,
122
(
6
), pp.
1516
1522
.
16.
Bates
,
J. H. T.
, and
Irvin
,
C. G.
,
2002
, “
Time Dependence of Recruitment and Derecruitment in the Lung: A Theoretical Model
,”
J. Appl. Physiol.
,
93
(
2
), pp.
705
713
.
17.
Jain
,
S. V.
,
Kollisch-Singule
,
M.
,
Sadowitz
,
B.
,
Dombert
,
L.
,
Satalin
,
J.
,
Andrews
,
P.
,
Gatto
,
L. A.
,
Nieman
,
G. F.
, and
Habashi
,
N. M.
,
2016
, “
The 30-Year Evolution of Airway Pressure Release Ventilation (APRV)
,”
Intensive Care Med. Exp.
,
4
, p.
11
.
18.
Allen
,
G. B.
,
Pavone
,
L. A.
,
DiRocco
,
J. D.
,
Bates
,
J. H.
, and
Nieman
,
G. F.
,
2005
, “
Pulmonary Impedance and Alveolar Instability During Injurious Ventilation in Rats
,”
J. Appl. Physiol.
,
99
(
2
), pp.
723
730
.
19.
Albert
,
S. P.
,
DiRocco
,
J.
,
Allen
,
G. B.
,
Bates
,
J. H. T.
,
Lafollette
,
R.
,
Kubiak
,
B. D.
,
Fischer
,
J.
,
Maroney
,
S.
, and
Nieman
,
G. F.
,
2009
, “
The Role of Time and Pressure on Alveolar Recruitment
,”
J. Appl. Physiol.
,
106
(
3
), pp.
757
765
.
20.
Smith
,
B. J.
,
Lundblad
,
L. K. A.
,
Kollisch-Singule
,
M.
,
Satalin
,
J.
,
Nieman
,
G.
,
Habashi
,
N.
, and
Bates
,
J. H. T.
,
2015
, “
Predicting the Response of the Injured Lung to the Mechanical Breath Profile
,”
J. Appl. Physiol.
,
118
(
7
), pp.
932
940
.
21.
Massa
,
C. B.
,
Allen
,
G. B.
, and
Bates
,
J. H. T.
,
2008
, “
Modeling the Dynamics of Recruitment and Derecruitment in Mice With Acute Lung Injury
,”
J. Appl. Physiol.
,
105
(
6
), pp.
1813
1821
.
22.
Kollisch-Singule
,
M.
,
Jain
,
S.
,
Andrews
,
P.
,
Smith
,
B. J.
,
Hamlington-Smith
,
K. L.
,
Roy
,
S.
,
DiStefano
,
D.
,
Nuss
,
E.
,
Satalin
,
J.
,
Meng
,
Q.
,
Marx
,
W.
,
Bates
,
J. H. T.
,
Gatto
,
L. A.
,
Nieman
,
G. F.
, and
Habashi
,
N. M.
,
2016
, “
Effect of Airway Pressure Release Ventilation on Dynamic Alveolar Heterogeneity
,”
JAMA Surg.
,
151
(
1
), pp.
64
72
.
23.
Kollisch-Singule
,
M.
,
Emr
,
B.
,
Smith
,
B.
,
Roy
,
S.
,
Jain
,
S.
,
Satalin
,
J.
,
Snyder
,
K.
,
Andrews
,
P.
,
Habashi
,
N.
,
Bates
,
J.
,
Marx
,
W.
,
Nieman
,
G.
, and
Gatto
,
L. A.
,
2014
, “
Mechanical Breath Profile of Airway Pressure Release Ventilation: The Effect on Alveolar Recruitment and Microstrain in Acute Lung Injury
,”
JAMA Surg
,
149
(
11
), pp.
1138
45
, Sep 17.
24.
Kollisch-Singule
,
M.
,
Emr
,
B.
,
Smith
,
B.
,
Ruiz
,
C.
,
Roy
,
S.
,
Meng
,
Q.
,
Jain
,
S.
,
Satalin
,
J.
,
Snyder
,
K.
,
Ghosh
,
A.
,
Marx
,
W. H.
,
Andrews
,
P.
,
Habashi
,
N.
,
Nieman
,
G. F.
, and
Gatto
,
L. A.
,
2014
, “
Airway Pressure Release Ventilation Reduces Conducting Airway Micro-Strain in Lung Injury
,”
J. Am. Coll. Surg.
,
219
(
5
), pp.
968
976
.