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� 2002 – Hubmayr – AJRCCM; 165: 1647–1653

� It is remarkable how little is known about alveolar deformation

during breathing.

� Most believe that alveoli unfold in the tidal breathing range and

only get stretched at high lung volumes .

� Others believe that only the alveolar ducts expand during

breathing,

� whereas alveolar volume and surface area remain more or less

constant.

� These uncertainties place substantial constraints on analyses of

alveolar mechanics in injury states

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� Inhalation

� Active process

� Diaphragm and intercostal muscles contract to increase thoracic

volume vertically creating a NEGATIVE change in thoracic pressure.

� At end inhalation alveolar pressure equalizes with atmospheric

pressure (approximately 0 cmH2O)

� Exhalation:

� Passive process

� Lungs recoil, thoracic volume decreases.

� At end exhalation alveolar & interstitial pressures return to

atmospheric (approximately 0 cmH2O)

� 2016 – Naik – Resp Care; 60(8): 1203–1210

� Spontaneous ventilatory pattern (Vt, Rate & I:E) controlled by the

medullary Ventilatory Control Center (VCC) and Modulator

� Modulator interacts to inputs from:

� Hypothalamus

� Amygdala

� Cerebral Cortex

� Limbic System

� Central Chemoreceptors

� Peripheral Aortic & Carotid Chemoreceptors

� Mechanoreceptors

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� 2016 – Naik – Resp Care; 60(8): 1203–1210

� Central Chemoreceptors

� Spinal fluid pH

� Peripheral Aortic & Carotid Chemoreceptors

� Blood PO2, PCO2 & pH

� Mechanoreceptors

� Stretch and irritant receptors

� 2016 – Naik – Resp Care 2015;60(8):1203–1210

� Mechanoreceptor Types

� Rapidly-adapting pulmonary stretch receptors

� Located in tracheobronchial mucosa

� Airway resistance, Reflex Apnea, Coughing

� Slowly-adapting pulmonary stretch receptors

� Located in tracheobronchial smooth muscle layer

� Activated by lung inflation

� Terminate inspiratory process

� Juxta-alveolar receptors

� Respond to mechanical & chemical irritation of pulmonary

interstitium

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� 2013 – Gilstrap – Am J Respir Crit Care Med; 188 (9): 1058–1068

� Ultimate ventilatory pattern generated by VCC:

� Adequate gas exchange

� Least amount of ventilatory muscle loading

� Least amount of air trapping

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� 1930’s

� Drinker-Shaw & Emerson negative-pressure tank machines introduced

� Cumbersome

� Pts needed to be able to maintain upper airway patency

� Could not support patients with oxygenation failure

� 1960’s

� Adult Respiratory Distress Syndrome (ARDS) first described

� Creation of modern Intensive Care Units

� Creation of ventilation with positive pressure

� 1967

� Puritan-Bennett MA-1 introduced

� Provided sighs

� 1970’s

� Partial ventilatory support - IMV

� Improved monitors & graphics

� Pressure-regulated modes introduced

� Variable flow demand

� 1980’s – 90’s

� Pressure Support Ventilation

� Lung-protective strategies introduced

� Permissive hypercapnea

� Vt limitation

� HFOV & HFJV

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� Just what is it that is delivered by the ventilator to the patients’ lungs?

� Volume

� Flow

� Pressure

� 2013 –Mireles-Cabodavila-Respir Care; 58(2): 348 –366

� PROVIDE GAS EXCHANGE SAFELY

� PRIMUM NON NOCERE

� PROVIDE COMFORT

� PROMOTE LIBERATION FROM THE VENTILATOR

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� Physics of positive-pressure ventilation differ radically from the physics

of spontaneous ventilation.

� During PPV inhalation:

� Positive intra-thoracic pressures

� Flow distributed heterogeneously throughout the lung

� Effectively distributed through compliant lung

� Attenuated in low-compliant areas

� This inspiratory flow heterogeneity can result in:

� Over-distension of compliant “healthy” lung

� Under-distension of non-compliant “injured” lung

� This damage is termed Ventilator-Induced Lung Injury (VILI)

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� 1744 – Fothergill:

� Described the mouth-to-mouth resuscitation of a coal miner

� May be the earliest description of ventilator-induced lung injury

� “The lungs of one may bear, without injury, as great a force as those of

another man can exert; which by the bellows cannot always be

determined”

� 1952 - Lassen – Lancet; 1;6749: 1-52

� Copenhagen polio outbreak

� Several problems with positive-pressure ventilation:

� “When bag ventilation is administered for weeks there is a risk of

emphysema”

� “The weaning period from positive-pressure ventilation is not

infrequently difficult”

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� 1967 – Nash – NEJM; 276.7: 368-374.

� Postmortem of patients who had undergone mechanical ventilation

� Alveolar infiltrates and hyaline membranes

� The term “Respirator Lung” coined

� 1970 – Mead – J Appl Physiol;28.5: 596-608.

� “In mechanical ventilation, by applying high transpulmonary

pressures to heterogeneously expanded lungs could contribute to

the development of lung hemorhage and hyaline membranes”

� 1972 - Pontoppidan – NEJM; 287.14: 690-698

� ARDS patients experienced discomfort when using small Vt’s.

� Beginning of the practice of using Vt’s in the 10-15 ml/kg range

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daviddarling.com

� 2013 – Biehl- Respir Care; 58(6): 927–934

� VILI = injury to the blood-gas barrier in the lung

� Caused by mechanical ventilation:

� Initial stretch of blood-gas barrier

� Disruption of pores in the endothelium

� Leakage of protein into the interstitial space

� Subsequent stretch of blood-gas barrier

� Membrane stress insult/failure

� Disruption of endothelium & alveolar epithelium

• Leakage of protein into alveolar space

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� 2017 – Nieman – Intensive Care Medicine Experimental ; 5; 8:1-21

� Three mechanisms for alveolar and alveolar duct injury during

mechanical ventilation:

� Over-Distension

� Dynamic Recruitment and De-recruitment

� Stress Concentration

� Occurs between open and collapsed or edema-filled alveoli

� Tissue damage, secondary to these mechanical injuries, results in a

secondary inflammatory injury (Biotrauma)

� For decades Barotrauma was considered as the major cause of VILI

� As long as Peak Inspiratory Pressures were maintained in the “safe”

range, the lungs were protected from injury

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� 1974 - Webb & Tierney – ARRD

� Two important concepts contrary to the barotrauma focus:

� Distending pressures & volumes above normal maximums

but below that which was required for alveolar rupture still

produced lung edema, surfactant abnormalities, tissue

inflammation and hemorrhage.

� Preventing cyclical alveolar collapse & reopening could also

significantly reduce the incidence of lung injury.

� Unfortunately, these concepts were not widely applied at the

time.

� 1988 – Dreyfus – ARRD

� Applied normal & excessive alveolar pressures to both volume-

limited lungs (chests bound to prevent alveolar expansion) and

volume-unlimited lungs (chests unbound with unchecked alveolar

expansion)

� Alveolar pressures caused considerably less lung damage in the

alveoli with limited expansion than in the alveoli in the unbound

chest.

� Alveoli that do not overdistend were unlikely to experience

damage

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� 1988 – Dreyfuss – AJRCCM; 137; 5: 201-223.

� Repetitive application of transalveolar pressures and tidal swings of

pressure (driving pressure) that substantially exceed those normally

encountered during normal tidal breathing will give rise to

hemorrhagic edema and inflammation that mimic ARDS

� 2016 – Nieman – Intensive Care Medicine Experiemental; 4:1: 1-6

� The mechanisms of VILI:

� Volutrauma - alveolar overdistenstion

� Atelectrauma - alveolar instability leading to alveolar collapse

and repopening with each breath

� Biotrauma – The secondary inflammation caused by these

mechanical trauma

• Measured “Lung Flooding” factors in rodents ventilated with three different ventilatory styles:

• HiP/HiV

• High Pressure (45 cmH2O)

• High Volume

• LoP/HiV

• Low Pressure (neg.pres.ventilator)

• High Volume

• HiP/LoV

• High Pressure (45 cmH2O)

• Low Volume (chest strapped)

Dreyfuss,D ARRD 1988;137:1159

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• 1988 – Dreyfuss – AJRCCM; 137; 5: 201-223.

• 2013 – Biehl – Respir Care; 58(6): 927–934

• Duration of exposure

• <24 h in large mammals

• Intensity of exposure

• Vt

• Too high → membrane strain/volutrauma

• FRC and the size of the available lung

• “Baby lung”

• PEEP

• Amount needed is influenced by prior recruitment and

chest-wall compliance

• 1988 – Dreyfuss – AJRCCM; 137; 5: 201-223.

• 2013 – Biehl – Respir Care; 58(6): 927–934

• Heterogeneity of Flow Distribution:

• Atelectasis

• Consolidation

• Edema

• End-inspiratory lung volume (FRC)

• Too low promotes derecruitment

• Too high promotes overdistension

• Inspiratory flow and flow profile (strain rate)

• Too high = ↓ risk of VILI

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• 1988 – Dreyfuss – AJRCCM; 137; 5: 201-223.

• 2013 – Biehl – Respir Care; 58(6): 927–934

• Breathing frequency

• Low RR = ↓ risk of VILI

• RR must be adequate to meet patient demand

• Most patients in ARF require 20-30 bpm to meet metabolic

needs

• Vascular pressures

• Higher transpulmonary pressures promotes higher hydrostatic

pressures

• ↑ risk of pulmonary edema

• 1988 – Dreyfuss – AJRCCM; 137; 5: 201-223.

• 2013 – Biehl - Respir Care; 58(6): 927–934

• The First “Hit”

• ↑ susceptibility to “second” hit of VILI

• Endotoxin/sepsis

• Tissue injury

• Fluid/transfusion

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� 1985 – Dreyfus – ARRD; 132.4: 880-884

� High Vt ventilation → pulmonary edema (permeability type)

� 2000 – Tschumperlin – AJRCCM; 162.2: 357-362.

� Limiting Vt’s ↓’s risk of injury of alveolar epithelium

� Large cyclic increases in alveolar surface area much more damaging

than static increases in alveolar surface area

� Alveolar epithelial viability is not adversely affected by application

of large static deformations (PEEP)

� Occasional deep inspirations to recruit collapsed alveoli should

not have a serious negative impact on alveolar epithelial viability.

� EXCESSIVE END-INSPIRATORY ALVEOLAR VOLUME IS THE MAJOR

DETERMINANT OF VOLUTRAUMA.

� Diffuse alveolar damage at the pulmonary/capillary membrane.

� ↑ epithelial & microvascular permeability → pulmonary edema

� May be indicated by excessive PPLAT

� May result from a combination of PEEP + Vt

� GOAL: Prevent excessive end-inspiratory volume

Slutsky, Chest, 1999

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� 2017 - Nieman –Intensive Care Medicine Experimental 5; 8:1-21

� Alveoli do not expand significantly with high volumes and pressures

� Disabuse yourself of the balloon picture

� Site of over-expansion and potential rupture may be the alveolar

duct, rather than the individual alveoli.

� 2011 – Seah – Ann Biomed Eng; 39.5: 1505-1516.

� Overdistension caused by high Vt does not cause VILI-histopathology

unless it was combined with high dynamic strain (with PEEP of 0).

� Increasing lung volume with PEEP actually decreased alveolar size,

while increasing alveolar number.

� 2015 – Chen – J Appl Physiol; 119; 3:190-201

� The role of gross alveolar over-distension (balloon-like overexpansion)

as the primary mechanism of VILI is in question

� Dynamic alveolar strain

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� CYCLICAL END-EXPIRATORY ALVEOLAR COLLAPSE/RE-EXPANSION IS THE

PRIMARY DETERMINANT OF ATELECTRAUMA

� 2003 – Bilik – J Appl Physiol; 94.2: 770-783.

� Repeated cyclical recruitment/de-recruitment of small airways/lung

units leads to abrasion of the epithelial airspace lining

� 2004 – Steinberg – AJRCCM; 169.1; 57-63

� Stabilizing alveoli with adequate PEEP significantly reduced VILI

� GOAL: Prevent end-expiratory alveolar de-recruitment

� 2016 – Marini – Critical Care Medicine; 44.1: 237-238.

� For the same Pplat, minimizing the number of collapsed units at

jeopardy is a key objective

� Lungs with extensive collapse need higher pressure to ventilate:

� Overstretch already open lung units

� Amplify tensions at the borders of open and closed lung units

� Amplified border tension & tidal opening/closure cycles deplete or

inactivate surfactant:

� Accentuate tissue tensions & tear delicate membranes

� Evoke inflammatory signaling in the endothelium &

microvasculature

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� EXCESSIVE FIO2 IS THE PRIMARY DETERMINANT OF OXYGEN TOXICITY

� Hazards of excessive FiO2

� Progressive alveolar damage & death 2° to generation of Reactive

Oxygen Species (ROS)

� ROS promotes formation of disruptive chemical bonds with

surrounding lipids, proteins and carbohydrates ↘

� Damage to cell membranes, collagen, connective tissue & DNA

� Alter enzymatic reactions within these tissues.

� Absorption atelectasis

• 1967 – Nash – NEJM; 276.7: 368-374

• Prolonged exposure to excessive FiO2 in mechanically ventilated pts:

• Worsens gas exchange

• Decreases ciliary efficacy

• Produces hyperoxic bronchitis and atelectasis

• 2012 – Rachmale – Respir Care; 57(11):1887–1893.

• Prolonged exposure to excessive FiO2 :

• Worse OI at 48 hrs.

• ↑ VLOS & ICU days

• May be associated with worsening lung function

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• 2016 – Girardis – JAMA On-Line; 316.15: 1583-1589

• RCT comparing:

• Conservative Oxygen therapy

• PaO2 70-100 / SpO2 94-98)

• Conventional

PaO2 <150 / SpO2 97-100

• Conservative group:

• ↓ episodes of shock, liver failure, and bacteremia.

• Significant ↓ mortality

• Study was terminated early

� EXCESSIVE TRANSPULMONARY PRESSURE ASSOCIATED WITH LUNG

OVER-DISTENSION IS THE PRIMARY DETERMINANT OF BAROTRAUMA

� Gross tissue injury permits transfer of air into the interstitial tissues.

� Clinically presents as:

� Pneumothorax

� Pneumomediastinum

� Pneumopericardium

� Subcutaneous emphysema.

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� Volutrauma

� End-Inspiratory Over-distension

� Destruction of Lung Tissue

� Increased Capillary Permeability

� Atelectrauma

� Cyclical End-Expiratory Collapse & Re-expansion

� Release of Inflammatory Mediators

� Surfactant dysfunction

� Increased regional over-distention and worsening

shunt

� Oxygen Toxicity

� Excessive FiO2

� Cytotoxic radicals

� Absorption Atelectasis

� Barotrauma

� Excessive Transpulmonary (not Airway)

Pressure

� Gross Air Leaks

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� 2015 – Amato – NEJM ;372:747-55.

� Retrospective analysis on the data from the ARDSNet ARMA study

� Vt, Pplat and PEEP had no correlation with mortality

� Driving Pressure (DPRS) correlated with ↑ mortality even in patients

receiving low-volume lung-protective ventilation

� May be a superior marker of VILI

� DPRS = PPLAT – PEEP

� Keep in mind – healthy lung compliance is about 80cc/cmH20 so…

� A 400cc Vt should only generate a driving pressure of about 5 cmH2O

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� The effect of chest-wall compliance was not included in the original

ARDSNet ARMA study nor the Amato retrospective analysis

� 2016 – Kassis – Int Care Med; 42:1206–1213

� Chest wall pressures may account for up to 33% of DPRS

� 2015 – Loring – NEJM; 372(8): 776–777.

� Driving Pressure of the Lung (DPL) takes into consideration the

effect of the Pleural Pressure impinging upon the lung by using

transpulmonary pressures in the equation:

� DPL = PTP PLAT - PTP PEEP

� 2015 – Loring – NEJM; 372(8): 776–777.

� DPL , instead of DPRS , may be the more appropriate measure of lung

injury due to the varying chest wall compliance and pleural

pressures between patients.

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� 2016 – Marini – Critical Care Medicine; 44.9: 1800-1801.

� Vt’s that are disproportionate to “baby” lung capacity require

transpulmonary pressures that produce damaging strains

� Inflation strain is not distributed uniformly throughout the lung

� Disproportionate stress occurs around relatively unyielding

points distributed widely in the injured lung

� Static stretching forces are amplified at these points

� Stress Focusing

� 2016 – Marini – Critical Care Medicine; 44.9: 1800-1801.

� When lung tissues fail to expand uniformly and some critical

threshold for strain is reached other variables become influential:

� Cycling frequency

� Flow amplitude

� Flow waveform

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• 2012 – Gattinoni – Current Opinion in Anesthesiology; 25:141–147

• Stress – distribution of distending forces per unit area

• In the lung this distending force is transpulmonary pressure

• Strain – deformation of an area in response to the stress applied

• 2016 – Protti – Critical Care Medicine; 44.9: e838-e845.

• Lung Strain – Ratio between Vt and FRC

• Lung Strain Rate – Ratio between Lung Strain and Ti

• Low Strain Rate – I:E of 1:2 – 1:3

• High Strain Rate – I:E of 1:9

• 2016 – Nieman – Intensive Care Medicine Experiemental; 4:1: 1-6

• “Individual mechanical breath parameters (e.g. Vt or Pplat) are not

directly correlated with VILI, but rather, any combination of

parameters that subject the lung to excessive dynamic strain and

energy/power load will cause VILI”

• All strain is not equal

• Dynamic Strain is more damaging than to lung tissue than static

strain

• Dynamic Strain = amount of the volume change caused by

Vt over the FRC

• Static Strain = volume change from PEEP over the FRC

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• 2016 – Nieman – Intensive Care Medicine Experiemental; 4:1: 1-6

• “Changing one single breath parameter , such as lowering Vt or Pplat,

will not protect the lung unless there is a concomitant reduction in

the Dynamic Strain”.

� 2011 – Schmidt – Crit Care Med; 39.9: 2059-2065

� Breathing discomfort is one of the stressful factors experienced and

remembered by the majority of mechanically-ventilated ICU patients

� Most patients report the discomfort as “air hunger”

� Manifests as anxiety and fear

� 2002 – Schelling – Neurobiol Learn Mem; 78.3 (2002): 596-609.

� Nearly 1 in 5 ICU survivors suffer from post-traumatic stress disorder

� Associated with mechanical ventilation and recall of dyspnea

� 2017 – Binks – Respiratory Care; 62(2):150 –155.

� Assessment of breathing discomfort in 30 ventilated patients

� RT’s, RN’s and MD’s routinely underestimated patients discomfort

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� 2013 – Gilstrap – Am J Respir Crit Care Med,188 (9), 1058–1068

� Respiratory muscle loading inherent in mechanical ventilation can

adversely effect the VCC through:

� Delayed or missed triggers

� ↑ inspiratory effort intensity & muscle load

� ↑ inspiratory muscle load

� Changes to spontaneous breathing pattern

� Rapid, shallow breathing

� Dyspnea

� Over-distension (mechanoreceptors)

� Shortening of neural Ti

� Activation of expiratory muscles

� 2017 – Binks – Respiratory Care; 62(2):150 –155.

� The simplest initial approach to detecting discomfort is to ask the

patient

� Determining discomfort in the non-verbal patient is challenging:

� Facial expression (particularly that of fear)

� Use of accessory muscles

� Nasal flaring

� Physiologic signs (HR & RR)

� 2008 – Campbell – J Palliat Med; 11:44–50

� Validation of the use of Respiratory Distress Observation Scale in

ventilated patients

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� Multiple strategies can be employed to improve patient/ventilator

synchrony during lung-protective ventilation:

� Sedation, Analgesia, Paralysis

� Adjust RR

� Adjust Vt

� Adjust trigger sensitivity

� Minimize Auto-PEEP

� Adjust PIFR

� Adjust Ti

� Adjust inspiratory flow cycling

� Adjust rise time

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