Identifying Microenvironment VILI and Optimizing the Mechanical Breath

71 The earliest description of what is now known as the acute respiratory distress syndrome 72 (ARDS) was a highly lethal double pneumonia. Ashbaugh and colleagues correctly identified the 73 disease as ARDS in a paper published in the Lancet in 1967. Their initial study, showing the 74 positive impact of mechanical ventilation with positive end-expiratory pressure (PEEP) on ARDS 75 mortality, was dampened when it was discovered that improperly used mechanical ventilation can 76 cause a secondary ventilator induced lung injury (VILI), greatly exacerbating ARDS mortality. This 77 Synthesis paper will review the pathophysiology of ARDS and VILI from a mechanical stress78 strain perspective. Although inflammation is also an important component of VILI pathology, it is 79 secondary to the mechanical damage caused by excessive strain. The mechanical breath will be 80 deconstructed to show that multiple parameters that comprise the breath airway pressure, flows, 81 volumes and the duration during each breath that they are applied – are critical to lung injury and 82 protection. Specifically, the mechanisms by which a properly set mechanical breath can reduce 83 the development of excessive fluid flux and pulmonary edema, which are a hallmark of ARDS 84 pathology, will be reviewed. Using our knowledge of how multiple parameters in the mechanical 85 breath impact lung physiology, the optimal combination of pressures, volumes, flows and 86 durations that should offer maximum lung protection, will be postulated. 87 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom Introduction (9,041 words – 10,000 limit) 88 The polio epidemic of 1916 inspired many treatment attempts including vitamin Chydroand 89 electrotherapy, but no effective therapy was found until Philip Drinker’s group invented negative 90 pressure mechanical ventilation – the iron lung. Their landmark paper was published in 1929, 91 entitled, “The use of a new apparatus for the prolonged administration of artificial respiration: I. A 92 fatal case of poliomyelitis,” demonstrating the effective clinical use of this device (Fig 1).(38) 93 Conversion from negative to positive pressure ventilation was based on the technical advances 94 made during World War II to deliver pressurized oxygen to high altitude fighter and bomber pilots. 95 Concomitant with these technologic advances in mechanical ventilation was the realization that 96 what was originally thought to be a universally fatal form of ‘double pneumonia’ was indeed a 97 unique clinical entity that we now call the acute respiratory distress syndrome (ARDS). In a 1967 98 seminal paper published in Lancet, Ashbaugh et. al. first identified and described ARDS as a 99 collection of pathologic abnormalities that can be caused by many unrelated insults such as 100 sepsis, hemorrhagic shock, pneumonia and trauma to name a few.(10) The disease and the 101 ventilator technology came together when it was shown that application of positive pressure 102 mechanical ventilation with the addition of an expiratory retard (Positive End Expiratory Pressure 103 PEEP), dramatically improved survival in patients with ARDS.(10) 104 The initial enthusiasm on the effectiveness of positive pressure ventilation for treating ARDS 105 was significantly dampened when it was found that the ventilator was a double-edged sword and if 106 used improperly could cause a ventilator induced lung injury (VILI)(136) that significantly 107 increased mortality.(8) Discovery that the ventilator can damage the lungs of patients with 108 established-ARDS, resulted in hundreds of studies investigating the molecular, cellular and 109 mechanical mechanisms of VILI.(128) These efforts culminated in the 2000 publication in the 110 NEJM demonstrating that reduced tidal volume and plateau airway pressure were positively 111 correlated with a reduction of ARDS mortality in a Phase III clinical trial.(8) However, recent 112 studies have shown that the ARDSnet low tidal volume strategy has not reduced mortality(105, 113 131, 134) and patients who survive ARDS have significant pulmonary(64) and cognitive 114 dysfunction.(91) Thus, the problem of VILI has not been solved. 115 Mechanical ventilation and the incidence of ARDS: Not only does VILI increase the morbidity 116 and mortality associated with ARDS(8) but improper ventilation of patients with normal lungs, at 117 high-risk of developing acute lung injury, significantly increases the incidence of ARDS (Fig 2).(35, 118 49, 52, 53, 66, 72, 119) However, if a protective mechanical breath is applied preemptively, during 119 the early acute lung injury (EALI) period, progression of acute lung injury may be halted and the 120 incidence of ARDS significantly reduced.(7, 50, 119, 120) 121 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom These studies illustrate four key concepts: 1) mortality in patients with established-ARDS 122 remains unacceptably high even with low Vt ventilation,(105, 131, 134) 2) improperly adjusted 123 mechanical ventilation can exacerbate EALI in patients at high-risk and thus increase ARDS 124 incidence(73) 3) preemptive application of a protective ventilation strategy in this same high-risk 125 group of patients can significantly reduce ARDS incidence,(7, 35, 49, 50, 52, 53, 58, 66, 72, 119) 126 and 4) the optimally protective breath necessary to block progressive acute lung injury remains to 127 be determined. 128 The inability to reduce the mortality of established-ARDS indicates that attention needs to shift 129 from treatment to prevention. However, the concept of preventing rather than treating ARDS is 130 new and the optimally protective mechanical breath remains illusive. Indeed, preemptive 131 ventilation using low Vt ventilation, the current standard of care in patients with established-ARDS, 132 has been shown to increase mortality in patients during major surgery and at high-risk of 133 developing acute lung injury.(72) This study suggests that ventilator strategies used to treat 134 established-ARDS(8) might not be optimal or even dangerous in patients with clinically normal 135 lungs but with early progressive acute lung injury.(72) 136 The Tetrad of ARDS Pathophysiology: Physiologists are in a very unique position to contribute 137 substantially to the identification of the optimal mechanical breath necessary to prevent ARDS 138 development. The key pathophysiologic mechanisms, which are the hallmarks of ARDS are 139 already well known. That is, we know the critical components of ARDS pathology, which make the 140 patient ‘sick’ are: 1) increased pulmonary capillary permeability,(62) 2) alveolar flooding with 141 edema,(86) 3) surfactant deactivation(67) and 4) altered alveolar mechanics(4) (i.e. the dynamic 142 change is alveolar size and shape during ventilation) [Fig 3]. We also know that improper 143 mechanical ventilation can exacerbate each component of this Pathologic Tetrad,(2, 23, 40, 47, 144 55, 124) which if unchecked can drive progressive acute lung injury into full-blown ARDS. Since it 145 has been shown that the mechanical ventilator can be adjusted in such a way to exacerbate or 146 minimize all of the tetrad pathologies,(2, 23, 40, 47, 55, 124) the physiologist needs to identify the 147 mechanism by which the mechanical breath damages lung tissue and, once known, design a 148 preemptive mechanical breath to prevent this damage. 149 The impact of mechanical ventilation on Tetrad pathology: Paradoxically, mechanical 150 ventilation during the EALI period can have the opposite effect on lung pathology depending on 151 ventilator settings; inappropriate settings can significantly increase the incidence of ARDS, while 152 application of a protective breath can reduce ARDS incidence.(7, 35, 49, 50, 52, 53, 66, 72, 119, 153 120)The challenge now is to determine how to precisely adjust the mechanical breath to prevent 154 the development of one or all of the Tetrad and thereby reduce ARDS incidence. In order to 155 accomplish this we need to first identify if there is sufficient time following the initiating injury (e.g. 156 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom trauma, sepsis, pneumonia, hemorrhagic shock) during which preemptive mechanical ventilation 157 can be applied. In other words is ARDS a progressive disease that can be treated early or is it 158 binary and the patient either has it or not? If ARDS is a progressive disease we then need to 159 identify how the parameters that comprise the Mechanical Breath Profile (MBP) (i.e. airway 160 Pressures, Volumes, Flows, Rates and the Duration that these parameters are applied to the lung 161 with each breath) can impact the pathophysiology of progressive acute lung injury. Once we know 162 the physiologic impact of each parameter comprising the mechanical breath on the pathologic 163 tetrad, we can generate hypotheses on the design of the optimally protective mechanical breath, 164 which if applied preemptively will block acute lung injury pathogenesis and reduce ARDS 165 incidence. 166 167 Early Acute Lung Injury (EALI) Pathogenesis 168 ARDS is a disease that progresses in stages: The original concept of ARDS is that it was 169 binary, either the lungs were ‘sick’ and you had ARDS or you didn’t; and thus lung protective 170 strategies (i.e. low Vt or proning) were implemented only after established-ARDS had 171 developed.(8, 22, 59) It is logical to expect that there must be a early acute lung injury (EALI) 172 phase with the identical pathologic mechanisms at work, but because a relatively small 173 percentage of the lung is damaged, combined with the ability of hypoxic pulmonary 174 vasoconstriction (HPV)(12) to match perfusion with patent alveoli, lung injury is not clinically 175 apparent (Fig 4, Stage 1).(112) 176 It has been shown that EALI begins even before the patient is placed on mechanical 177 ventilation.(48, 73) In addition, it was found that patients being ventilated on room air, who met 178 the American-European consensus conference (AECC) definition of ARDS,(13) no longer met 179 ARDS criteria with the addition of PEEP and increased FiO2.(46, 132) The ARDS that 180 “disappeared” with PEEP and increased FiO2 was termed Transient ARDS (Fig 4, Stage 2), while 181 that which did not disappear was termed Persistent or Established-ARDS (Fig 4, Stage 3). Thus, 182 just because patients meet the current criteria for established-ARDS, does not signify that they all 183 are at the same stage of ARDS development. 184 This concept has been further supported by recent literature investigating the early 185 development of ALI and the impact of the mechanical breath on disease progression.(35, 49, 51186 53, 63, 66, 119) These studies showed that patients who were placed on mechanical ventilation 187 for reasons other than respiratory failure developed more ALI/ARDS if they where ventilated with 188 higher airway pressures and tidal volumes. Also, patients without ALI on mechanical ventilation 189 for >48hr have a 19% chance of developing acute lung injury.(66) It is well known that patients 190 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom with truly healthy lungs, such as paralysis patients, can be placed on mechanical ventilation for 191 years without developing acute lung injury.(28) This suggests that, in patients on mechanical 192 ventilation that eventually develop ALI/ARDS the lungs are not “healthy” upon intubation; instead, 193 the lungs are in the EALI stage and the injurious components of the mechanical breath act as a 194 ‘2-hit’ to drive the progression of disease. For example, Wessem et al showed in a rat 195 hemorrhagic shock (HS) model that HS alone did not produce significant pulmonary inflammation 196 or lung injury unless it was combined with mechanical ventilation, which precipitated ARDS.(129) 197 These data demonstrate that ARDS is actually a disease that progresses in stages (Fig 198 4).(112) This fact, combined with the knowledge that ARDS almost always develops within the 199 hospital(121) and that once established is refractory to treatment,(82, 87) collectively support the 200 hypothesis that a preferred strategy should be to block the disease in an early stage rather than 201 treat it once developed. Indeed, Villar and Slutsky recently commented that, “ARDS is no longer 202 a syndrome that must be treated, but is a syndrome that should be prevented”.(133) 203 Pathophysiology of early acute lung injury (EALI): There is a large volume of data describing 204 the molecular, cellular, physiologic, and pathologic components of established-ARDS,(25, 32, 83, 205 117, 135) but little information on the pathogenesis during the EALI stages before the 206 development of clinical symptoms (Fig 4, Stage 1). Established-ARDS is characterized by: 1) 207 dysfunction of both the endothelial and epithelial barriers leading to, 2) high-permeability 208 pulmonary edema causing, 3) surfactant deactivation and 4) alveolar instability (Fig 3).(1, 25, 32, 209 83, 117, 122, 135) The components of the Pathologic Tetrad develop progressively and in a 210 heterogeneous fashion. Over time the pulmonary edema and surfactant loss will necessitate the 211 use of mechanical ventilation to maintain oxygenation, which will add another ‘hit’ (i.e. VILI with 212 inappropriate ventilation) exacerbating and accelerating lung damage. The impact of increased 213 alveolar flooding and surfactant deactivation results in: 1) Volutrauma, with small airways rupture 214 and pneumothorax, and 2) Atelectrauma, marked by alveolar collapse and reopening causing a 215 dynamic strain-induced injury to the pulmonary parenchyma.(96, 122) This mechanical damage 216 to lung tissue results in release of inflammatory mediators causing a secondary Biotrauma, which 217 is a significant component in ARDS pathogenesis.(127) Thus VILI is a combination of 218 Atelectrauma, Volutrauma, and Biotrauma. 219 Most of the data on EALI pathophysiology has come either from studies looking for markers of 220 patients at risk of developing ARDS(14, 15, 19, 26, 32, 36, 56, 65, 74, 99) or clinical studies 221 investigating the development of ARDS secondary to mechanical ventilation in patients with 222 presumably normal lungs.(16, 45, 48, 49, 51, 52, 66, 75, 119) Multiple inflammatory biomarkers 223 have been found in patients at high risk of developing ARDS giving us more clues to EALI 224 pathophysiology.(32, 85) Not surprisingly the same mediators associated with established-ARDS 225 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom are also associated with patients at high risk of developing the syndrome. E-selectin(99), reduced 226 levels of surfactant protein-A and –B (SP-A,-B)(56) as well s as tumor necrosis factor (TNF),(65) 227 Interleukin-6 and -8 (IL-6, -8),(19, 36) variant angiopoietin-2 (ANG2),(90) have all been found in 228 the plasma or bronchoalveolar lavage fluid (BALF) of patients before they were clinically 229 diagnosed with ALI/ARDS. These data suggest that the same pulmonary pathophysiology is 230 taking place before the clinical symptoms of ALI/ARDS are present. Thus, it is likely that increased 231 endothelial(76, 100), and epithelial(24, 76) permeability, surfactant deactivation,(56) pulmonary 232 edema(71) and altered alveolar mechanics suggested by chest X-ray and oxygen 233 requirements(73), are all occurring unnoticed before the patient is diagnosed with ALI/ARDS, 234 generating the conditions that will ultimately drive the Pathologic Tetrad. 235 Ventilator induced lung injury (VILI) drives progressive acute lung injury: It is known that very 236 high Vt combined with low PEEP will cause VILI in normal lungs with the pathology 237 indistinguishable from the injury seen in ARDS(25, 117) suggesting that a significant portion of 238 ARDS pathology is ventilator induced.(37) At the very least, the initial lung injury caused by direct 239 (pneumonia, aspiration) or indirect (trauma, sepsis, hemorrhagic shock) inflammation works 240 synergistically with inappropriate mechanical ventilation to drive disease progression significantly 241 increasing the incidence, morbidity and mortality of ARDS.(102) Indeed, it has been theorized 242 that, “Acute Lung Injury (ALI)/ARDS is a consequence of our efforts to ventilate patients, rather 243 than progression of the underlying disease”.(133) Strong clinical evidence supports this 244 hypothesis, since the only treatment in a Phase III clinical trial that demonstrated a significant 245 reduction in ARDS mortality, was by decreasing Vt(8) and using low Vt in combination with 246 proning.(59) These studies demonstrated that minimizing the VILI component of ARDS could 247 improve survival.(8, 59) Since it is known that the mechanical breath can be made less harmful 248 depending on the combination and magnitude of the breath parameters (Vt, Pplat, PEEP), it is not 249 a conceptual leap to postulate that further optimization of the mechanical breath may actually be 250 protective and prevent ARDS before it develops. This supports the likelihood that properly 251 adjusted mechanical ventilation can be used as a therapeutic tool to prevent rather than treat 252 established-ARDS(130, 131, 133) 253 There is evidence that the lungs of patients placed on mechanical ventilation without clinical 254 ALI were not normal but rather a significant portion of lung was already damaged and in an EALI 255 stage, even though the criteria for ALI or ARDS had not been met (Fig 4, Stage 1).(44) Gajic,(52, 256 53) Determann(35) and Jia et al(66) independly showed that many ICU patients placed on 257 mechanical ventilation, but who did not meet ALI/ARDS criteria, nevertheless had significant 258 signs of EALI such as the need for increased FiO2 and high peak airway pressures, low 259 PaO2/FiO2 (P/F) ratios, acidemia, and elevated plasma levels of IL-6. In addition, patients on 260 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom mechanical ventilation without AECC defined ALI, showed a positive correlation between high 261 airway pressures and tidal volume (Vt) and the development of established-ARDS, suggesting 262 that VILI is in progress during the EALI stage and significantly contributing to the pathology (Fig 263 4, Stage 1).(49) Indeed, patients without clinical ALI (Fig 4, Stage 1) who are intubated would 264 likely be placed on non-protective ventilation with higher Vt, further accelerating ARDS 265 development. 266 In a recent clinical study patients that had undergone extensive abdominal surgery, but with 267 normal lungs, were placed on one of two mechanical ventilator settings, 1) Vt 12 + PEEP0 or 2) 268 Vt 6-8 + PEEP 6-8 with a recruitment maneuver and the incidence of major complications 269 recorded in each group. There were significantly more complications in the non-protective group 270 (Vt12+PEEP0) including acute respiratory failure (ARF), pneumonia, sepsis, septic shock and 271 death.(50, 120) This study supports the early works suggesting that the settings on the 272 mechanical ventilator play a critical role in the development of acute lung injury in patients with 273 normal lungs, but at high-risk due to systemic inflammation. Finally in a recent review paper 274 Fuller et al. summarize the role of mechanical ventilation in the development of ARDS by 275 concluding that: 1) higher Vt is causal in the development of ARDS, 2) ARDS occurs early in the 276 course of mechanical ventilation and thus prevention trials should also occur early, and 3) the 277 development of ARDS is associated with significant morbidity and mortality, suggesting that 278 ARDS-prevention trials are needed.(49) 279 It is clear from the above that non-protective mechanical ventilation can greatly accelerate the 280 progression, as well as increase the incidence of ARDS. It is the hypothesis of our lab(7, 41, 68, 281 69, 111-113) and multiple other investigators(16, 45, 48-52, 58, 66, 73, 119, 120) that if a 282 protective mechanical breath is applied early, the incidence of ARDS can be significantly reduced. 283 What remain to be determined are the settings needed to optimize protective mechanical 284 ventilation. 285 What do we need to know to block progressive acute lung injury: There is sufficient evidence 286 that lung pathology, identical to that seen in established-ARDS, is unfolding hours or days before 287 the clinical manifestations of the disease.(14, 15, 19, 26, 32, 36, 56, 65, 73, 74, 90, 99) In addition, 288 if mechanical ventilation with currently acceptable tidal volumes and pressures is applied during 289 this period it can act as a ‘2-Hit’, exacerbating lung injury and resulting in a higher prevalence of 290 established-ARDS; however, if slight changes in Vt or PEEP are applied early, then the incidence 291 of established-ARDS is reduced.(16, 45, 48, 49, 51, 52, 66, 75, 119) These data, in addition to the 292 fact that almost all ARDS develops in the hospital(121) support the concept that preemptive 293 application of a protective mechanical breath can block progressive acute lung injury and reduce 294 ARDS incidence. The next critical step is to ascertain: 1) the precise mechanism of ventilator295 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom induced damage to the pulmonary microenvironment – the alveoli and alveolar ducts and 2) once 296 the mechanism is known, identify the settings that would optimize the protective mechanical 297 breath, thus preventing injury. 298 299 Identifying Microenvironment VILI and Optimizing the Mechanical Breath 300 Microenvironment VILI 301 Structural design of the alveolus and alveolar duct: The healthy lung is a homogeneously 302 ventilated organ that is structurally resistant to mechanical damage during ventilation. The shared 303 walls of each alveolus with a two-fiber support system (i.e. the axial system anchored to the hilum 304 and extending into the alveolar ducts and the peripheral system anchored to the visceral pleura 305 distending into the central portion of the lung) are structurally very stable and resistant to either 306 over-distension or collapse (Fig 6).(137) The concept of this alveolar interdependence was first 307 introduced by Mead et al. and describes the structural mechanisms by which alveoli resist either 308 collapse (Fig 7B) or hyperinflation (Fig 7D).(88) In addition, they also demonstrate how 309 heterogeneous collapse of alveoli create stress-concentrators in the areas between open and 310 collapse alveoli (Fig 7B). These stress-concentrators greatly amplify the mechanical damage to 311 tissue in the transitional zone between open and collapsed or edema filled alveoli.(31, 109) 312 Microenvironment VILI mechanical or inflammatory: The logical sequence of events in 313 progression of acute lung injury caused by inappropriate mechanical ventilation would seem to be 314 mechanical damage to pulmonary tissue caused by excess stress-induced strain as the primary 315 injury, followed by Biotrauma in response to physical damage caused by excessive strain.(33, 316 140) D’Angelo et al showed that ‘low volume lung injury’ was caused by cyclic opening and 317 closing of small airways and not by release of inflammatory cytokines.(33) Likewise, Yoshikawa et 318 al demonstrated that alveolar hyper-permeability occurred rapidly following exposure to high peak 319 inflation pressure (PIP), and was initially independent of an increase in inflammatory mediators 320 (TNF-α, IL1β, IL-6 and MIP-2), thus supporting the hypothesis that mechanical damage (dynamic 321 strain and stress-concentrators) causes the initial damage followed by a secondary inflammatory 322 injury.(140) Ultimately, this mechanical insult results in the release of inflammatory mediators, 323 which exacerbate the primary mechanical damage resulting in a secondary Biotrauma.(122) 324 However, it appears the key to preventing VILI is to block the mechanical insult to alveoli and 325 alveolar ducts. To do this we need to understand if the mechanism of mechanical injury is caused 326 by over-distension or dynamic strain of the pulmonary fine structures. 327 Microenvironment VILI – dynamic strain or over-distension: Most studies have shown that a 328 high static airway pressure sufficient to significantly distend the lung, in the absence of dynamic 329 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom strain due to collapse of alveoli during expiration, will not cause ARDS-like histopathology and 330 edema. Multiple studies have shown that high static strain associated with lung over-distension 331 alone (i.e. in the absence of dynamic strain) does not result in tissue histopathology typical of 332 ARDS, even though it may cause rupture of small airways leading to pneumothorax.(108, 118) 333 However, with the identical total strain, increasing the dynamic strain component causes 334 histopathology and pulmonary edema characteristic of ARDS (Fig 8).(108) 335 The majority of the studies that measured change in alveolar size with high airway pressure 336 showed a relative alveolar enlargement with increased airway pressure, however, alveolar size 337 remained well within the range of normal alveolar anatomy.(27, 89) These studies are supported 338 by physiologic evidence that high static strain, which should be sufficient to cause over-distension 339 induced tissue damage, is benign unless this strain is dynamic.(108, 118) Large high Vt causing a 340 high static strain with sufficient PEEP to prevent high dynamic strain (i.e. large changes in alveolar 341 volume with each breath) cause minimal lung injury. However, if PEEP is reduced creating 342 excessive dynamic strain, significant lung damage will occur at the identical peak static strain (Fig 343 8).(108) Thus, it appears that dynamic strain or Atelectrauma is the primary mechanical 344 mechanism of injury to the pulmonary parenchyma. Volutrauma is also important because it can 345 cause stress-failure in small airways leading to pneumonthoraces but does not cause pulmonary 346 edema or histopathology to the pulmonary parenchyma (Fig 8). 347 More recently another mechanical VILI mechanism has been identified.(104, 109) Evidence 348 has shown that the damage to the pulmonary parenchyma can be caused by heterogeneous 349 ventilation, which occurs at the junction between collapsed(109) or edema filled(104) alveoli and 350 air inflated alveoli. This heterogeneity causes stress-concentrators that can significantly magnify 351 the amount of alveolar and alveolar duct strain for any given stress and thus appear to be another 352 mechanism of mechanical injury to the pulmonary tissue (Fig 5).(104) The main pathologic cause 353 for both heterogeneous ventilation and altered alveolar and small airway mechanics is airway 354 flooding with edema fluid and altered surfactant function (Fig 3). Ventilator-induced loss of 355 surfactant function(2) exacerbates edema formation,(20, 95) which deactivates more surfactant. 356 (97) This leads to alveolar instability, which aggravates vascular permeability,(40) causing more 357 edema, deactivating more surfactant, in a cycle that repeats until established-ARDS is recognized. 358 However, if a mechanical breath can be applied preemptively to maintain homogeneous lung 359 ventilation (eliminate stress-concentrators) and prevent alveolar collapse and reopening during 360 ventilation (eliminate dynamic strain), it would ameliorate all components of the pathologic tetrad 361 and theoretically reduce ARDS incidence (Fig 3) 362 Thus, physiologic evidence suggests that applying a preemptive mechanical breath directed to 363 maintain homogenous lung inflation and not allowing alveoli to collapse during expiration, 364 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom progressive acute lung injury may be blocked. Lachmann in 1992 identified the optimal way to 365 protect the patient with established-ARDS from VILI as, ‘Open up the Lung and Keep the Lung 366 Open’.(70) To reduce the incidence of ARDS in patients at high-risk using mechanical ventilation 367 this statement should be modified to, ‘Never Let the Lung Collapse’. 368 369 Physiologic evidence that the mechanical breath can block progressive acute lung injury 370 Acute lung injury causes a pathologic alteration in terminal airspace, generating extreme 371 strains on the tissues in this microenvironment (i.e. alveoli and alveolar ducts). Excessive tissue 372 strain results in a secondary VILI, which significantly increases ARDS incidence and mortality. 373 Preemptive mechanical ventilation can minimize this severe strain and block progressive acute 374 lung injury. A component of this pathology is pulmonary edema, which is a hallmark of ARDS (Fig 375 3B).(1, 25, 32, 83, 117, 122, 135) Is it possible that the same MBP that minimizes tissue strain 376 can also reduce pulmonary edema deposition? 377 Parameters comprising the Mechanical Breath Profile (MBP): There are at least ten 378 components comprising the mechanical breath profile (MBP) and it is likely that a complex 379 relationship among these components play a critical role in either preventing or inflecting lung 380 injury. The 10 parameters comprising the MBP are: Time at Inspiration (TI), Pressure at Inspiration 381 (PI), Time at Expiration (TE), Pressure at Expiration (PE), Transition Time from PE to PI (∆TI), 382 Transition Time from PI to PE (∆TE), Respiratory Rate (RR), Tidal volume (Vt), Inspiratory Flow 383 (Qi), and Expiratory Flow (QE). In addition, the volume of the lung at expiration (Functional 384 Residual Capacity – FRC) and at inspiration (% of Total Lung Capacity – TLC) is likely to influence 385 the effect of the mechanical breath at the alveolar level. Until we understand how all of the 386 components in the MBP impact the pulmonary parenchyma, we will not be able to scientifically 387 manipulate the mechanical breath to be optimally protective. 388 Lung fluid balance and ARDS pathophysiology: In order to identify if the MBP that minimizes 389 tissue strain will reduce pulmonary edema we must refer to the Starling Equation for fluid flux and 390 the mechanism of ARDS-induced edema formation. The major components of the Starling 391 Equation (Eq 1) are the hydrostatic and oncotic pressure gradients between the capillary lumen 392 and the surrounding interstitial tissue, the capillary surface area available for fluid flux, and the 393 permeability of capillary membrane to liquids and proteins. Trauma or sepsis-induced systemic 394 inflammation (SIRS) can increase vascular permeability, which results in edema-induced 395 surfactant deactivation, both of which can cause a disruption in fluid balance described by the 396 Starling equation (Eq 1). 397 398 Jv = Lp•PS [(Pc Pi) – σ(πp – πi)] (Eq 1) 399 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom 400 Capillary filtration rate (Jv) is governed by the balance between capillary hydrostatic pressure 401 (Pc) and plasma colloid osmotic pressure (πp), interstitial hydrostatic pressure (Pi) and colloid 402 osmotic pressure (πi), hydraulic conductivity (Lp), surface area available for filtration (PS) and 403 vascular permeability expressed as a reflection coefficient (σ) (Eq 1). The combination of low 404 capillary hydrostatic pressure (~7mmHg) and plasma osmotic pressure (~28mmHg) provide a 405 strong absorptive force. This positive gradient for absorption is partially offset by a high-baseline 406 tissue protein concentration (πi) that reduces the effective transcapillary colloid osmotic 407 absorptive pressure [σ(πp – πi)]. The overall result is a slight gradient favoring fluid movement 408 out of the capillaries.(54) 409 SIRS disrupts this delicate balance by increasing the vascular permeability (σ), causing a shift 410 toward an increased capillary filtration rate (Jv), and by increasing alveolar surface tension, 411 resulting in a decrease in interstitial hydrostatic pressure (Pi).(39, 54, 101) Recently this classic 412 Starling equation has been modified to incorporate what is defined as the glycocalyx model of 413 transvascular fluid flux.(138) In both Starling models the fluid flux occurs due to transendothelial 414 pressure difference [(Pc Pi). The difference between the classic and glycocalyx Starling models 415 is that the plasma – interstitial colloid osmotic pressure (COP) differences, in the modified 416 Starling model fluid flux is governed by transendothelial pressure difference and the plasma – 417 subglycocalyx COP (πsg) difference (πp – πsg) rather than the COP difference between plasma 418 and the interstitial space (πp – πi). 419 Multiple parameters of the MBP could affect various components of the Starling equation 420 including Pc, Pi, πsg, and σ, which could dramatically impact lung fluid balance. In addition, the 421 mechanical breath can also directly damage pulmonary epithelial and endothelial cells by 422 mechanical distortion secondary to micro-stress/strain(124) and inhibit or deactivate pulmonary 423 surfactant.(2) An inappropriately set MBP can exacerbate lung fluid flux by multiple mechanisms, 424 which would explain the ventilator dependent increase in ARDS mortality.(8) Conversely, 425 appropriately adjusted ventilation can minimize stress-concentrators(104, 109) and dynamic 426 strain(68, 69) and has been shown to reduce ARDS incidence.(58, 119) Thus, is it possible that 427 parameters in the MBP can be set to not only minimize micro-strain but to concurrently reduce 428 edema formation? 429 To understand the impact of the MBP on lung fluid balance physiology we must recognize the 430 unique relationship of the alveolar (AV) and extra-alveolar (EAV) vessels within the lung in their 431 response to positive alveolar pressure delivered by mechanical ventilation. This understanding is 432 key since alveolar pressure and lung inflation have opposite effects on fluid exudation from AV vs. 433 EAV. AV capillaries collapse with increased alveolar airway pressure.(77) Extra-alveolar vessels 434 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom are larger than capillaries (~100 μm) and expand with increased airway pressure and lung volume 435 due to a reduction in the interstitial pressure (Pi). Alveolar corner vessels have similar dimensions 436 as AVs (10-20μm) but like EAVs expand with increased lung volume.(77) Thus increased airway 437 pressure and lung volume would collapse AVs, reducing the permeability surface area (PS) and 438 increase the Pi surrounding these vessels, both of which would decrease fluid exudate. On the 439 other hand the same mechanical breath would decrease the Pi surrounding the EAVs and corner 440 vessels, expanding the vessels and increasing fluid exudation. When the lung is fully inflated 441 approximately 1/3 of the total fluid filtration comes from each of the 3 vessel types (AVs, venous-, 442 and arterial-EAVs).(3) Luchtel et have shown that the interstitial space surrounding extra-alveolar 443 veins is contiguous with that of the extra-alveolar arteries and edema fluid which leaks from these 444 collects up in the peri-arterial cuffs.(77) They also showed that the arterial extra-alveolar 445 interstitium plus lymphatics within this interstitium are important for edema drainage, and thus lung 446 volume may be an important edema safety factor. 447 Overview MBP and pulmonary edema: The literature investigating the effect of the MBP on 448 lung fluid balance have almost exclusively focused on only 2 (Vt and PEEP) of the 10 MBP 449 components. The majority of studies focused on the impact of changes in End-Expiratory 450 Pressure (PEEP)(23, 29, 37, 47, 55, 78, 93, 106, 115, 116, 136) with a smaller number 451 investigating the impact of Vt and PEEP on lung fluid balance.(23, 29) The data demonstrate 452 that, if sufficient preemptive PEEP is applied, lung water will be significantly diminished in 453 multiple lung injury models including: high vascular pressure,(23, 47, 106, 116) high alveolar 454 surface tension,(78) high endothelial permeability(29, 55, 93, 115) and high airway pressure.(37, 455 136) Also PEEP is most effective at reducing edema when applied soon after the injury. (47, 114) 456 Studies demonstrating that PEEP does not prevent edema applied low levels of PEEP (8457 10cmH2O) and sometimes reduced this level during the experiment, applied PEEP after edema 458 had already developed, and often used what we have now identified as injurious tidal volumes 459 (15-20ml/kg).(17, 103, 107) Clinical trials have also shown no benefit of high PEEP when applied 460 in patients with established-ARDS where edema has presumably already developed.(21, 103) 461 This suggests that not only does the combination and magnitude of the MBP parameters play a 462 role in lung fluid balance but also the timing of application in the course of the disease is critical to 463 lung protection. 464 There are numerous possible mechanisms by which PEEP might impact lung fluid balance and 465 edema formation. PEEP increases the vascular transmural pressure secondary to an increase in 466 the interstitial hydrostatic pressure (Pi, Eq 1) opposing fluid movement out of the capillaries.(47, 467 116, 136) For example, in an isolated perfused pig lung preparation Schumann et al 468 hypothesized high pulmonary vascular pressure would result in edema but that PEEP would 469 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom prevent the increase in lung water.(116) The results of the experiment were mixed with PEEP (8 470 cmH2O) reducing edema with low perfusion pressures (hydrostatic reservoir 65cm) but not at 471 high perfusion pressures (hydrostatic reservoir 105cm). The authors suggest that one reason 472 why edema was not reduced with high vascular pressure may be the use of a relatively low 473 PEEP (8 cmH2O) and that higher values of PEEP, above the hydrostatic pressure in the 474 vasculature, may yield different results. This makes sense since with very high Pc generated by 475 the reservoir set at 105cm, PEEP level would have to be sufficiently elevated to raise the Pi to a 476 level at or above Pc in order to reduce fluid flux. Russell et al showed in an isolated perfused dog 477 lung with oleic acid injury that PEEP must be higher than pulmonary artery pressure to prevent 478 edema.(115) 479 PEEP may act to support the integrity of the interstitial matrix. An intact interstitial matrix 480 functions as a low compliance glove surrounding the capillary and plays a key role in restricting 481 capillary fluid filtration.(92) As long as the extracellular matrix is intact, edema is contained within 482 the interstitial space. Severe edema develops rapidly once damage to the extracellular matrix 483 reaches a critical ‘tipping point’ when the fluid restrictive component of the matrix is lost, allowing 484 rapid efflux of fluid from the capillaries through the interstitial and into the alveolar space.(5, 94) 485 The pressure transmitted to the interstitial space (Pi, Eq 1) with PEEP would prevent edema 486 swelling-induced injury to the extracellular matrix, maintaining this important ‘edema safety 487 factor’, preventing the rapid influx of edema and alveolar flooding. These data clearly show that 488 one component of the MBP, PEEP, can reduce edema accumulation, which is a key pathologic 489 component of ARDS (Fig 3). 490 It is known that edema can be caused by four basic mechanisms: high capillary pressure, high 491 alveolar surface tension, high capillary endothelial permeability and high alveolar epithelial 492 permeability. It is important to know if adjustments to the MBP can prevent or reduce pulmonary 493 edema accumulation secondary to all four mechanisms, since they may play active role in clinical 494 ARDS pathogenesis. 495 MBP (PEEP) effects on high vascular pressure edema: Multiple studies have shown that PEEP 496 can reduce edema accumulation caused by increased vascular pressure (Pc, Eq 1).(23, 47, 106, 497 116) Mondejar et al used a dog model and elevated pulmonary capillary hydrostatic pressure (Pc, 498 Eq1) by increasing left atrial pressure (Pla).(47) They demonstrated that a PEEP of 10 or 20 499 cmH2O, applied 30 minutes after Pla was increased, prevented further accumulation of edema 500 (but did not reduce the edema that existed before PEEP application); a PEEP of 20 cmH2O 501 applied 90 minutes after Pla was elevated did not prevent edema.(47) Thus, PEEP was effective 502 only if applied early in the course of the disease. They also showed that 10 but not 20 cmH2O 503 PEEP increased thoracic duct lymph flow. The mechanism of reduced edema was hypothesized 504 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom to be a reduction in the transmural pressure gradient [Pla – pleural pressure (Ppl)] where Pla is 505 an approximation of Pc and Ppl an approximation of Pi [(Pc-Pi), Eq 1]. 506 Bshouty et al used an in situ canine upper lobe preparation and tested the impact of tidal 507 volume (Vt), PEEP and lung volume on edema formation secondary to elevated vascular 508 pressure.(23) They hypothesized that changes in Vt may effect fluid filtration (Jv) but not by the 509 mechanism of changing lung volume. Specifically they postulated that increased Vt would reduce 510 edema since higher lung volume reduces fluid filtration (Eq 1) and increases fluid removal 511 secondary to increased lymph flow. Surprisingly their data demonstrated that the rate of edema 512 formation (∆W/∆t) was significantly increased with higher (as compared with lower) Vt, but if 513 mean airway pressure was elevated by raising PEEP to levels equal to those during high Vt, the 514 rate of edema formation fell below baseline levels. 515 They reasoned that Vt-induced edema was not due to reduced lymph flow but rather an 516 increase in permeability (Lp) or area (PS) or both without changing Pi, πc, πi, or σ. They came to 517 this conclusion because Pcrit (i.e. the critical pressure needed to initiate lung weight gain 518 measured as the intercept of the linear regression of vascular pressure and edema formation) 519 was unaffected during the development of edema (Eq 1). ∆W/∆t increased with large Vt and 520 decreased with PEEP despite the fact that Effective Filtration Pressure (EFP) was not 521 significantly different. Since the increase in lung volume was the same in both high Vt and high 522 PEEP but the effect on ∆W/∆t were in the opposite direction the mechanism could not be due to 523 differences in microvascular surface area. 524 The main difference between the two lung volumes was that the large Vt was associated with a 525 high lung volume during part of the cycle, and a low volume during the remainder of the ventilator 526 cycle. Since the rate of ∆W/∆t was higher with dynamic ventilation, these data suggest that the 527 impact of lung volume on fluid flux is not linear but rather functions in a nonlinear fashion, with a 528 much greater impact on fluid flux taking place at higher volumes. It is possible that the change in 529 Pi with lung inflation may be time dependent and thus sustained pressures (PEEP) have a 530 greater effect on Pi than dynamic pressure cycles (high Vt). Increasing Pi would decrease fluid 531 filtration and reduce edema accumulation, which may be the mechanism of sustained PEEP532 induced reduction in edema formation. 533 These studies demonstrate that both Vt and PEEP can reduce edema caused by increased 534 vascular pressure. In addition, the Bshouty study supports our current understanding of the MBP 535 parameters that are key to lung protection.(23) Their data showed that dynamic strain caused by 536 high Vt caused more edema than a static strain at the same pressures caused by high PEEP. 537 Their data also suggest that the impact of the MBP on Pi is time dependent and thus PEEP is 538 more protective since a higher airway pressure is applied to the alveolus over a longer period of 539 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom time during each breath. This supports the current studies showing that an extended time at 540 inspiration and a minimal time at expiration reduces ARDS incidence in animals(41, 111-113, 541 123) and in trauma patients at high-risk of developing acute lung injury.(7) 542 MBP (PEEP) effects on High Surface Tension and Edema: Luecke et al in a sheep surfactant 543 deactivation ARDS model (saline lavage) showed by thermal dye dilution technique that 544 sequentially increasing PEEP (0,7,14, or 21cmH2O) effectively reduced pulmonary edema 545 measured as the extravascular lung water (EVLW). Following saline lavage, lungs were 546 ventilated with 0 cmH2O PEEP for 60 min to establish lung injury and then PEEP was increased 547 in 60-min intervals. They demonstrated that PEEP effectively reduced pulmonary edema 548 accumulation. Some edema had already developed following surfactant washout before 549 application of PEEP and this edema was not reduced. This supports the findings in high vascular 550 pressure edema(47, 114) that PEEP is most effective at preventing edema before it develops. 551 Albert recently published a hypothesis stating that ventilation (mechanical or spontaneous) 552 induced deactivation of surfactant is the initiating pathologic event in EALI rather than increased 553 alveolar capillary permeability, which ultimately leads to established ARDS.(2) If this hypothesis 554 is correct then mechanical ventilation is the initiating factor in the development of ARDS and thus 555 blocking at this point will significantly reduce incidence. 556 It is well established that mechanical ventilation with large Vt and low PEEP can cause 557 irreversible compression of surfactant causing surfactant molecules to be driven toward the 558 airways resulting in surfactant depletion, and that elevating PEEP reduces or prevents this 559 deactivation.(42, 57, 84, 136, 139) Maruscak et al showed that mechanical ventilation with low 560 stretch (Vt 8ml/kg + PEEP 5cmH2O) prevented surfactant deactivation as compared with high 561 stretch (Vt 30ml/kg + PEEP 0 cmH2O). More importantly, they demonstrated that alterations in 562 surfactant were a consequence of the ventilation strategy and thereby contribute directly to lung 563 dysfunction over time.(81) Arolod et al demonstrated that variable ventilation in a saline lavage 564 ARDS model improved oxygenation, increased surfactant and attenuated alveolar protein 565 concentrations without the need for high airway pressures and volumes.(9) Surfactant 566 deactivation secondary to mechanical ventilation can be slowed or prevented by application of 567 sufficient PEEP. Malloy et al showed in sepsis-induced lung injury that application of PEEP 568 (5cmH2O) significantly reduced surfactant deactivation and preserved lung function.(80) Thus, 569 surfactant dysfunction caused by inappropriate mechanical ventilation could be the ‘engine’ that 570 drives progressive acute lung injury. However, just slighting modifying the MBP by increasing 571 PEEP or decreasing Vt can have a dramatic effect on preventing ventilation-induced surfactant 572 deactivation and on accumulation of pulmonary edema. 573 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom MBP and vascular permeability: Many studies have also shown that altering the MBP can 574 reduce edema formation in high vascular permeability-induced edema.(29, 55, 93, 115) In a pig 575 oleic acid model Colmenero-Ruiz showed that application of PEEP (10cmH2O) immediately 576 following oleic acid infusion reduced pulmonary edema, and that a concomitant reduction in Vt 577 further reduced the accumulation of lung water.(29) Similarly, Russell et al showed that if PEEP 578 were set higher than the pulmonary artery pressure, edema would be blocked in an in situ 579 isolated perfused lung model with oleic acid injury.(115) One possible mechanism is that PEEP 580 normalizes σ by stabilizing alveoli and thus preventing the cyclic stretch of the alveolar 581 endothelium.(34, 61) It has been shown that rapid Ca entry through transient receptor potential 582 vanilloid-4 (TRPV4) channels is the major determinant of an increase in alveolar capillary 583 permeability.(61, 98) TRPV4 receptors are stretch sensitive and are thus likely candidates for 584 stretch-activated increase in alveolar capillary permeability secondary to cyclic stretch (i.e. 585 alveolar instability) during tidal ventilation.(5) Another mechanism could be elevation of Pi and 586 shifting the balance of the Starling equation away from fluid egress from the capillaries even with 587 an increase in σ. This hypothesis is supported by the work of Russell et al, who demonstrated 588 that if PEEP were higher than pulmonary artery pressure then edema would be prevented.(115) 589 MBP and complex pathophysiology: Pulmonary edema caused by an increase in vascular flow 590 and pulmonary artery pressure (35mmHg) was significantly reduced with the edition of PEEP 591 (15cmH2O), however, the protective impact of PEEP was lost when a second-hit (Oleic Acid) was 592 infused into the circuit of an isolated perfused rabbit lung preparation.(106) These data suggest 593 that edemogenic factors are cumulative and that altering a mechanical breath parameter, in this 594 case increasing PEEP to prevent edema following a single insult, may not be effective with 595 multiple insults. This is an important concept since sepsis or trauma patients are often exposed to 596 many edemogenic alterations (i.e. changes in vascular permeability, increased vascular 597 pressures with fluid and blood infusions, reduction in plasma oncotic pressures) concomitantly. 598 In a study using HCl instillation to increase Lp, σ, and alveolar surface tension in dogs, it was 599 shown that surfactant replacement combined with PEEP was necessary to reduce edema 600 accumulation.(142) Exogenous surfactant treatment, PEEP or both were applied 1hr after HCl 601 injury. The edema that accumulated before treatment was not reduced, again supporting the 602 hypothesis that protective ventilation only works if applied very early, but further increases in 603 edema were prevented only in the Surfactant+PEEP group. Although Lp and σ were not directly 604 measured they felt that there was no mechanism that could explain surfactant or PEEP-induced 605 normalization of these values that were very likely altered by exposure to HCl. They conclude 606 that reestablishment of normal surface tension would increase pulmonary interstitial pressure (Pi, 607 Eq 1), reduce the hydrostatic pressure gradient across the extra alveolar vessels, and thus 608 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom prevent further edema formation. PEEP was necessary to open alveoli and redistribute edema so 609 that the exogenous surfactant could reestablish normal surface tension on the alveolar surface. 610 In addition, PEEP would also increase Pi and thus would work additively or synergistically with 611 lowering alveolar surface tension. Lastly, they hypothesized that the combination of PEEP and 612 surfactant replacement might result in a more homogeneous ventilation, restoring alveolar 613 interdependence (Fig 7)(88) and thus reducing the development of stress-concentrators.(104, 614 109) 615 This hypothesis was supported by Corbridge et al who showed that lowering Vt + increasing 616 PEEP significantly reduced edema in a HCl-induced lung injury model in dogs.(30) Surfactant 617 function was assessed using whole lung pressure volume curves and they hypothesized that the 618 larger Vt and lower PEEP depleted surfactant, which was preserved by reducing Vt and 619 increasing PEEP. An alternative hypothesis would be that the low PEEP and higher PEEP 620 opened the lung reducing stress-concentrators and minimize dynamic strain by preventing 621 alveolar collapse and reopening. It is very possible that minimizing strain injury to the alveolus 622 combined with preservation of surfactant function worked synergistically to reduce edema 623 formation. 624 Summary: Modification of the MBP early in ARDS pathogenesis can reduce the amount of 625 pulmonary edema. The vast majority of studies have only investigated singularly the role of one 626 MBP parameter, positive end-expiratory pressure or PEEP on edema development. These 627 studies have shown that adequate PEEP applied early can block edema accumulation in high 628 capillary pressure, high alveolar surface tension, high airway pressure and high permeability 629 induced lung injury. Deconstruction of the entire mechanical breath will be necessary to identify 630 the optimal combination of MBP parameters, in addition to PEEP, necessary to optimally prevent 631 edema formation. In conjunction with using mechanical ventilation to reduce edema formation 632 conservative fluid management should also be part of the total treatment package.(110) 633 634 Optimizing the mechanical breath 635 Designing the optimally protective mechanical breath: To effectively block progressive acute 636 lung injury we must use the physiologic knowledge that the primary mechanisms of VILI are 637 stress-concentrators and dynamic strain and design a mechanical breath that will block both. 638 There is a critical need to identify the impact of the mechanical breath on pathophysiology at the 639 alveolar level; if we overlook alveolar function we, in fact, would subject our patients to ventilation 640 by trial and error. An inappropriately set mechanical breath intensifies the pathologic tetrad (Fig 3), 641 exacerbating the damage caused by either primary (pneumonia) or secondary (sepsis, trauma, 642 hemorrhagic shock) injuries that can progress into established-ARDS. A major reason why 643 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom identification of this optimally protective breath has been so difficult is the reductionist approach 644 used in an attempt to answer the question. The mechanical breath is comprised of multiple 645 parameters (i.e. airway Pressures, Volumes, Rates, Flows and the Duration that these parameters 646 are applied during each breath) all of which individually and in combination may cause structural 647 damage to the alveoli. The current standard-of-care ventilation for established-ARDS focuses on 648 only 3 of these breath parameters: 1) tidal volume (Vt), plateau airway pressure (Pplat) and 649 positive end-expiratory pressure (PEEP).(8) In order to identify the optimally protective breath we 650 need to deconstruct the mechanical breath and determine what parameters, in what combination, 651 and at what magnitude, minimize the pathologic progression of acute lung injury. 652 Time a key MBP parameter in lung protection: In principle, the combination of MBP parameters 653 that would maintain a homogeneously ventilated lung and alveolar stability would be most 654 protective. A mechanical breath with an extended duration at inspiration (TI) during each breath 655 would in theory recruit and maintain lung homogeneity. A small tidal volume (Vt) or a very short 656 duration at expiration (TE) would theoretically stabilize alveoli, preventing subsequent collapse and 657 reopening. It could be argued that the MBP that would seem to maximize both of these 658 components may be high frequency oscillatory ventilation (HFOV). However, early application of 659 HFOV in patients with acute lung injury did not improve clinical outcomes and indeed actually 660 increased mortality.(43, 141) From a purely physiologic perspective it is hard to understand why 661 these studies did not show improvement, since this MBP was targeted to what we currently believe 662 to be the primary mechanisms of mechanical damage to the lung parenchyma. It has been 663 postulated that the lack of efficacy in these studies was not due to failure to prevent mechanical 664 damage to the pulmonary parenchyma, but rather by multiple other factors including 665 hemodynamic compromise in the HFOV group requiring increased pressor medication end-organ 666 failures and application after rather than before established lung injury.(79) 667 Multiple studies have shown that a combination of low Vt, recruitment maneuvers and PEEP 668 do reduce the incidence of ARDS in ICU and surgery patients at high-risk.(7, 35, 49, 50, 52, 53, 669 58, 66, 72, 119) The low Vt breath should reduce dynamic alveolar strain but may not be as 670 effective as HFOV at homogeneous lung ventilation (which would reduce stress-concentrators) 671 unless recruitment maneuvers with sufficient PEEP were added to prevent the newly opened 672 alveoli from recollapsing.(60) Although HFOV was applied during early ARDS, the patients 673 nevertheless had significant lung injury at the time of treatment. In all of the preemptive low Vt 674 studies the treatment was applied prophylactically, when the lungs were still normal. This 675 suggests that the timing of the treatment may be essential to improved outcomes. 676 A major problem with the current standard of care ARDSnet ventilation is that it is a one-size677 fits-all strategy with all patients receiving a Vt of 6cc/kg and a sliding PEEP and FiO2 scale based 678 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom on oxygenation.(8) Thus, the ability to personalize the mechanical breath to the lung pathology of 679 each patient remains a significant clinical problem. The Open Lung Strategy, attempts to 680 personalize the mechanical breath by optimally setting PEEP following a recruitment maneuver 681 (RM) based on physiologic parameters including best dynamic tidal compliance ,(125) best 682 PaO2,(18) best stress index,(126) and upper and lower infection points.(6) Although sound in 683 principle there are multiple problems with this approach: 1) it is not preemptive and sufficient lung 684 damage has already occurred necessitating a RM, 2) there can be negative side effects so RMs 685 cannot be conducted very often, 3) since RMs can be applied so infrequently the lung may re686 collapse resulting in heterogeneous ventilation, and 4) alveoli may become more unstable with 687 disease progression such that the PEEP initially necessary to prevent alveolar collapse may no 688 longer be sufficient, resulting in alveolar μ-strain induced lung damage. 689 Black et al have shown that dynamic respiratory resistance and elastance can be used to 690 personalize the PEEP setting to each patient.(11) This study demonstrates that dynamic 691 respiratory mechanics are very sensitive to mechanical heterogeneities in the lung and that 692 minimizing mechanical heterogeneities, with personalized PEEP, maximizes PaO2 and minimizes 693 peak-to-peak airway pressure.(11) Another possible technique to personalize the protective breath 694 is the use of the expiratory flow curve to identify changes in lung mechanics with APRV.(111) It 695 has been shown that using the expiratory flow curve to set the time at expiration (TLow) will 696 stabilize alveoli(68, 69, 113) and reduce acute lung injury.(113) Combined these studies show 697 that it is possible to personalize the protective breath to lung pathology. 698 The role of an extended duration during inspiration (TI) and minimal duration at expiration (TE) 699 on reducing ARDS incidence was tested in multiple animal models and in a clinical meta700 analysis.(7, 41, 68, 69, 111-113) In these studies the airway pressure release ventilation (APRV) 701 mode was used as a tool to precisely control the duration of inspiration and expiration. As with 702 HFOV, an extended TI and minimal TE should maintain homogeneous ventilation and prevent 703 alveolar collapse using APRV. The animal studies clearly show that a MBP with this time profile 704 will indeed reduce ARDS incidence(41, 111-113) and this suggests that the mechanism of 705 protection is by reducing both stress-concentrators (Fig 5) with homogeneous inflation and by 706 minimizing dynamic strain by preventing subsequent alveolar collapse and reopening with each 707 breath (Fig 9).(68) Computational model confirmed that this time dependent MBP with an extend 708 time at high pressure and minimal time at low pressure both recruited and stabilized alveoli.(123) 709 Although the only clinical study investigating this time-dependent MBP was a statistical analysis, it 710 clearly demonstrated a reduction in ARDS incidence as compared with the current standard of 711 care in 16 other hospitals.(7) It is important to note that in these animal experiments the time712 dependent MBP was applied when the lungs were still clinically normal.(41, 111-113) Thus, these 713 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom studies support the clinical evidence that early application of low Vt and PEEP will reduce ARDS 714 incidence in high-risk ICU and surgery patients.(58, 119) 715 Summary: The homogeneously ventilated lung is structurally sound and alveoli are very 716 resistant to over-distension or collapse (Fig 6,7).(88, 137) However, trauma, sepsis or 717 hemorrhagic shock can result in a serious systemic inflammatory response syndrome (SIRS) that 718 initiates a pathologic tetrad (Fig 3,(4, 62, 67, 86) which significantly disrupts normal homogeneous 719 ventilation resulting in stress-concentrators (Fig 5)(104, 109) and dynamic strain (Fig 9).(68) If 720 preemptive mechanical ventilation is applied following SIRS but before clinical symptoms of the 721 Tetrad, the incidence of ARDS can be reduced (Fig 2).(58, 119) The entire Mechanical Breath 722 Profile (MBP) must be deconstructed in order to determine the optimal breath to reduce ARDS 723 incidence. Currently, physiologic studies suggest that a MBP with an extended time at inspiration 724 and minimal time at expiration is optimal at blocking progressive acute lung injury.(41, 111-113) 725 One systematic review supports this finding in trauma patients.(7) 726 727 728 Conclusions 729 Once established, ARDS is refractory to treatment with only low Vt and proning showing any 730 improvement in mortality in Phase III clinical trials. Even with these treatment strategies it has 731 been shown that ARDS mortality has not significantly declined remaining recalcitrant at near 732 40%.(105, 131, 134) Evidence shows that ARDS is a progressive disease and if treatment is 733 applied early then disease progression can be blocked. Numerous clinical studies have shown 734 that a combination of low Vt, lung recruitment, and PEEP applied in ICU and surgery patients with 735 normal lungs but at high-risk will significantly reduce ARDS incidence.(58, 119) However, one 736 study has shown that low Vt with low PEEP actually increased mortality and thus the optimally 737 preemptive mechanical breath necessary to block progressive acute lung injury remains 738 unknown.(72) Studies in several animals models(41, 111-113) and a clinical statistical analysis(7) 739 have shown that a mechanical breath with an extended duration at peak inspiration and minimal 740 duration at end expiration is effective at reducing ARDS incidence, suggesting that the parameter 741 of time during which the airway pressures are applied to the lung in each breath is a important 742 component in lung protection. The primary mechanical mechanisms of progressive acute lung 743 injury are: 1) stress-concentrators on alveolar walls between adjacent air filled and collapsed or 744 edema filled alveoli, 2) dynamic strain on alveolar walls during collapse and reopening, and 3) 745 stress-failure of over-distended small airways with high pressure leading to pneumothorax. The 746 mechanical breath that will be effective at preventing this mechanical injury must convert a 747 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom heterogeneously to a homogeneously ventilated lung, in order to eliminate stress-concentrators 748 and prevent alveolar collapse and reopening, thus minimizing dynamic strain. This must be done 749 without having to apply excessively high airway pressures to prevent airway stress-failure. In 750 addition to minimizing mechanical damage to the lung, a properly adjusted mechanical breath can 751 reduce or prevent pulmonary edema development and preserve surfactant function, both of which 752 are hallmarks of ARDS pathophysiology. Application of such a Mbp before the lung is injured and 753 remodels may also be critical. Combined, these data suggest that the properly adjusted 754 mechanical breath can dramatically reduce the mechanical damage to the lung known as VILI and 755 also prevent two of the primary pathologies associated with ARDS, pulmonary edema and 756 surfactant deactivation. 757 Future work must expand upon the current reductionist strategy of testing the protective 758 potential of just one mechanical breath parameter at a time. The entire mechanical breath profile 759 (MBP) containing all airway pressure, flows, volumes, rates and the time during each breath that 760 these parameters are applied to the lung, must be analyzed concomitantly in order to identify the 761 optimally protective breath. Some of the MBP parameters have been shown to reduce mechanical 762 damage to lung tissue and reduce edema and preserve surfactant function. Low Vt, adequate 763 PEEP, an extended duration at peak pressure and minimal duratiion at end expiration have all 764 been shown to be important components in the protective mechanical breath. Ultimately we need 765 to identify what mechanical breath parameters, in what combination and at what magnitude are 766 most effective at preventing progressive acute lung injury. Once the MBP is identified and applied 767 to all patients before the onset of lung injury, the incidence of ARDS may be reduced to near zero. 768 769 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom 770 Legends: 771 772 Figure 1. The Iron Lung as seen in the initial paper by Drinker et al first describing the clinical use of 773 negative pressure mechanical ventilation. Permissions to republish granted. (38) 774 775 Figure 2. Kaplan-Meier curve describing the incidence of acute lung injury in patients placed on 776 mechanical ventilation before the development of acute lung injury with conventional tidal volume 777 (solid circles) or lower tidal volume (open circles). Open Access article permission granted.(35) 778 779 Figure 3. Pathology Tetrad of ARDS pathophysiology: A) increased pulmonary vascular permeability, 780 B) pulmonary edema, C) surfactant deactivation and D) altered alveolar mechanics (i.e. the dynamic 781 size and shape change of the alveolus during tidal ventilation). A) Increased pulmonary capillary 782 permeability measured by positron emission tomography (PET) scan normal patient and a patient 783 with ARDS. Structural injury is shown as an increase in extravascular density (EVD, top scale 0-80) of 784 the ARDS lung with a ventral-dorsal gradient (white vs black arrows). Change in vascular permeability 785 is described as the pulmonary transcapillary escape rate (PTCER, bottom scale 0-500) and is wide 786 spread in nature. PTCER suggests that the lung in the ARDS patient is much more diffuse then 787 suggested by the functional injury (EVD) and may explain why the ARDS lung is so vulnerable to 788 VILI.(62) B) Injured (edematous) and Normal (aerated) lungs with the changes in mechanical 789 properties caused by edema analyzed by magnetic resonance elastography (MRE). Lung volume 790 was assessed using T1-weighted sin echo. Shear wave propagation within an elastic or viscoelastic 791 medium can quantify and spatially resolve the elastic properties of the lung. The shorter wavelengths 792 in the Injured lung suggest that the lung is more compliant due to the edema and deactivation of 793 surfactant function. This study demonstrates that both edema and surfactant deactivation play a key 794 role in ARDS pathophysiology and that edema can be spatially located using MRE,(86) C) not only is 795 loss of surfactant function on the alveolar surface a key component in ARDS pathophysiology(2) but 796 this study demonstrates the importance of the surface tension between the air filled alveolar duct and 797 the edema fluid in a flooded alveolus.(67) Heterogeneous ventilation with air filled alveoli (A) adjacent 798 to edema filled alveoli (F) create stress-concentrators, which would result in a dynamic alveolar wall 799 bowing into the edema filled alveoli causing mechanical damage to the alveolar tissue. If a rhodamine 800 dye that lowers the surface tension on the air-liquid interface the liquid will flow out of the alveolus (* = 801 newly aerated alveolus) eliminating the stress-concentrator preventing damage to alveolar tissue, and 802 D) altered lung mechanics typical of ARDS have been ascribed to altered mechanics at the alveolar 803 level. In this study dynamic subpleural alveolar mechanics were measured using in vivo 804 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom videomicroscopy. Alveolar mechanics (i.e. the dynamic change in alveolar size and shape during tidal 805 ventilation) were correlated with lung mechanics as measured by elastance (H), impedance and 806 hysteresivity (η). It was concluded that simultaneous increase in both H and η are reflective of lung 807 injury in the form of alveolar instability, whereas an increase in just H reflects merely derecruitment of 808 alveoli. Permissions to republish granted. (4) 809 810 Figure 4: Theoretical pathogenesis of ARDS development from Normal (N) to established-ARDS 811 (Stage-3). Stage Column = stage of ARDS development, Column A = diagram of alveoli, interstitial 812 space and capillary; Column B = the percent of the entire lung that these lesions occupy; and Column 813 C = the clinical presentation at each stage. Stages 1 and 2 we define as pre-ARDS and Stage 3 is the 814 current ARDSnet definition of ARDS. Stage Column: N = Normal Alveoli no interstitial or alveolar 815 edema; 1 = Stage-1 (Early Acute Lung Injury EALI) interstitial edema in vascular cuffs (grey) 816 without alveolar flooding or measurable clinical symptoms; 2 = Stage-2 (insidious-ARDS) interstitial 817 edema (light grey) and partial flooding of alveoli (dark grey) with moderate surfactant deactivation 818 (dotted lines) causing alveolar instability and hypoxemia. Insidious-ARDS has all of the Clinical 819 Parameters of established-ARDS except hypoxemia is not refractory if ventilation with the appropriate 820 Mechanical Breath Profile (MBP) is applied; and 3 = Stage-3 (established-ARDS) interstitial edema 821 (light grey) and complete alveolar flooding with edema (black), severe surfactant deactivation and all 822 Clinical Parameters as defined by the ARDS consensus conference including refractory hypoxemia 823 even if appropriately set mechanical breath is applied. Figure adapted from Roy et al. Permissions to 824 republish granted.(112) 825 826 Figure 5. An example of stress-concentration between an air-filled and edematous alveolus. A) A 827 model of the forces between Air-filled and Air-filled alveoli. Alveolar pressure is depicted as Palv. A 828 thin liquid hypophase with liquid pressure lines each alveolus (Pliq). The radius (R) of the air-liquid 829 interface is a straight line and thus infinite. All forces are in balance in adjacent air-filled alveoli and 830 thus the septum is planar. B) A model of the forces between an Air-filled and Edematous alveolus. 831 The Meniscus results in a smaller radius (R2) in the edematous alveolus as compared with the Air832 filled alveolus (R1). The difference in radius generates a greater pressure drop across the Air-filled 833 alveolar interface, which in turn results in a lower liquid phase pressure (Pliq2) in the Edematous 834 alveoli (Pliq1). The difference in Pliq causes the septum to ‘bulge’ toward the Edematous alveoli 835 causing excessive strain. Permissions to republish granted. 836 837 Figure 6. Alveolar and alveolar duct architecture with the connective tissue systems (i.e. axial fibers 838 seen as helical structure and peripheral fibers extending to the pleural surface). Note the 839 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom interdependence of alveolar shared walls that maintain structural integrity as long as homogeneously 840 inflated. Arrow depicts the distending action of surface tension. Permissions to republish 841 granted.(137) 842 843 Figure 7. Diagrammatic description of alveolar interdependence. Shared alveolar walls in 844 homogeneous inflated lung (A) resist alveolar collapse (B) and overexpansion (C, D). Note the 845 additional strain on the alveoli surrounding the center collapsing alveoli (B), which is the source of 846 stress-concentration. Permissions to republish granted. (88) 847 848 Figure 8. Demonstration that high dynamic (VT 100% VPEEP 0%) but not high static (VT 25% VPEEP 849 75%) strain causes ARDS, assessed by development of pulmonary edema (Lung weight). Pigs were 850 ventilated for 54hrs with an identical peak strain near Total Lung Capacity (TLC) using a combination 851 of VT and PEEP. When the strain was applied using VT without PEEP a high dynamic strain was 852 subjected to the lung with each breath (VT 100% VPEEP 0%). Static strain was applied by use of 853 elevated PEEP with greatly reduced VT (VT 25% VPEEP 75%). ARDS was assessed by a change in 854 lung weight (i.e. pulmonary edema) from the baseline measurement (Initial) and at the end of the 855 experiment (Final). All animals subject to dynamic strain developed pulmonary edema whereas 856 animals with the identical static strain, but with minimal dynamic strain, did not. Permissions to 857 republish granted.(108) 858 859 Figure 9. Impact of 4 different mechanical breath strategies on both dynamic alveolar strain (DS) and 860 generation of stress-concentrators (S-C). In vivo videomicroscopy of subpleural alveoli in a surfactant 861 deactivation model of ARDS was used to identify areas of S-C (i.e. areas of heterogeneous alveolar 862 ventilation) and DS (i.e. a large change in alveolar size during tidal ventilation). Inflated alveoli were 863 colored yellow and collapsed alveoli appear as an amorphous red mass. The areas of both inflated 864 and collapsed alveoli were measured using computer image analysis. A) Photomicrographs of the 865 same subpleural alveoli at Inspiration and Expiration subjected to 4-different mechanical breath 866 strategies: 1) Low Vt (6cc/kg) + PEEP 5 (cmH2O), 2) Low Vt + PEEP 16, 3) airway pressure release 867 ventilation (APRV) with the time at expiration (TLow) set inappropriately long at Ratio 10% of the ratio 868 of termination of peak expiratory flow rate (T-PEFR) to the peak expiratory flow rate (PEFR) and 4) 869 APRV with an appropriately set very short TLow at Ratio 75% T-PEFR/PEFR. Heterogeneous 870 ventilation is defined as collapsed alveoli adjacent to inflated and have been show to generate stress871 concentrators.(109) B) Alveolar homogeneity and stability were assessed as the percent of the 872 microscopic field occupied by inflated alveoli at Inspiration and Expiration. Few alveoli were open at 873 inspiration with Low Vt +PEEP 5 (high S-C) and many alveoli collapsed and reopened during 874 by 10.2.32.246 on O cber 4, 2017 http://jaysiology.org/ D ow nladed fom ventilation (high DS). APRV Ratio 10% resulted in homogeneous alveolar inflation (low S-C) at 875 Inspiration but many alveoli collapsed during expiration (high DS). Low Vt PEEP 16 did not result in 876 homogeneous alveolar inflation at Inspiration (high S-C) but did stabilize alveoli (low DS). APRV Ratio 877 75% resulted in homogeneous ventilation (low S-C) and alveolar stability (low DS). 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