Physiologic Effects of Noninvasive Ventilation

Neil R MacIntyre

Introduction
NIV Can Augment Minute Ventilation
NIV Unloads Ventilatory Muscles
NIV Resets the Ventilatory Control System
Alveolar Recruitment and Gas Exchange
Other Physiologic Effects of NIV: Intended and Unintended
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Maintaining Upper-Airway Patency

Reducing Imposed Triggering Loads From Auto-PEEP
Cardiac Interactions: Both Beneficial and Harmful
Ventilator-Induced Lung Injury
Production of Auto-PEEP
Patient-Ventilator Interactions
Summary

Noninvasive ventilation (NIV) has a number of physiologic effects similar to invasive ventilation.
The major effects are to augment minute ventilation and reduce muscle loading. These effects, in
turn, can have profound effects on the patient’s ventilator control system, both acutely and chron-
ically. Because NIV can be supplied with PEEP, the maintenance of alveolar recruitment is also
made possible and the triggering load imposed by auto-PEEP can be reduced. NIV (or simply mask
CPAP) can maintain upper-airway patency during sleep in patients with obstructive sleep apnea.
NIV can have multiple effects on cardiac function. By reducing venous return, it can help in patients
with heart failure or fluid overload, but it can compromise cardiac output in others. NIV can also
increase right ventricular afterload or function to reduce left ventricular afterload. Potential det-
rimental physiologic effects of NIV are ventilator-induced lung injury, auto-PEEP development, and
discomfort/muscle overload from poor patient–ventilator interactions. Key words: invasive ventilation;
noninvasive ventilation; minute and alveolar ventilation; ventilation distribution; ventilation-perfusion match-
ing; control of ventilation; ventilatory muscles; work of breathing; patient–ventilator interactions; ventilator-
induced lung injury. [Respir Care 2019;64(6):617–628. © 2019 Daedalus Enterprises]

Introduction this definition, this discussion will focus on positive-pres-

sure devices with a mask interface to either totally or partially
Noninvasive ventilation (NIV) is the process of support-
ing respiration using devices that do not require an artifi-
cial airway. While a variety of external chest devices meet
Dr MacIntyre presented a version of this paper at the 57th RESPIRATORY
CARE Journal Conference, held June 14-15, 2018, in St Petersburg, Florida.

Dr MacIntyre is affiliated with the Division of Pulmonary and Critical Care Correspondence: Neil R MacIntyre MD FAARC, Division of Pulmonary
Medicine, Duke University Medical Center, Durham, North Carolina. and Critical Care Medicine, Duke University Medical Center, Box 3911,
Durham, NC 27710. E-mail: [email protected].
Dr MacIntyre has disclosed relationships with Ventec, Breathe, and
InspiRx. DOI: 10.4187/respcare.06635

RESPIRATORY CARE • JUNE 2019 VOL 64 NO 6 617

 PHYSIOLOGIC EFFECTS OF NIV

provide O2 and CO2 transport between the environment and ther way, the minute ventilation (V̇E) delivered to the pa-
the pulmonary capillary bed.1,2 NIV is often coupled with tient can be increased substantially.
PEEP to maintain positive airway pressure throughout the Unless there is a marked increase in dead space (V̇D)
ventilatory cycle. The primary desired effect of NIV is to with positive-pressure ventilation, an increased V̇E from
maintain adequate levels of PO2 and PCO2 in arterial blood NIV usually translates to an increased alveolar ventilation
while also unloading the inspiratory muscles. (V̇A ⫽ V̇E ⫺ V̇D). The net effect of an increased V̇A is to
NIV has many of the same physiologic effects as inva- provide additional O2 to and remove additional CO2 from
sive ventilation (ie, through an artificial airway). However, alveolar gas. Mathematically, the relationship of V̇A to
there are important differences. First, because of inherent alveolar gas partial pressures are:
leaks, NIV systems cannot always supply volumes and
pressures comparable to invasive ventilation, despite so- PaO2 ⫽ PIO2 ⫺ 共V̇O2/V̇A兲 ⫻ k
phisticated leak-compensation features. These leaks can
also affect triggering sensitivity and patient–ventilator syn-
chrony during flow delivery and breath cycling. Second, PaCO2 ⫽ 共V̇CO2/V̇A兲 ⫻ k
NIV is applied to the oronasal pharynx that connects to the
esophagus as well as the trachea. Despite the presence of where PIO2 is inspired oxygen, V̇O2 is total body oxygen
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gastroesophageal sphincters, high positive esophageal pres- consumption, V̇CO2 is total body CO2 production, and k is
sures can lead to gastric distention. Third, the unprotected a constant. These relationships are depicted in Figure 1
trachea, especially in the setting of a distended stomach, is and show that, as V̇A increases, alveolar PO2 asymptotes on
exposed to significant aspiration risk. Fourth, the absence the PIO2 and alveolar PCO2 asymptotes on zero.10
of an artificial airway also limits the effectiveness of air- Gas transport across the alveolar capillary membrane is
way suctioning and pulmonary toilet. Fifth, with single- driven by gradients between alveolar and venous blood
lumen circuits relying on controlled leaks for exhalation, gas tensions and alveolar capillary membrane diffusing
the potential for CO2 re-breathing exists, especially if flow properties. In general, with a normal blood transit time in
settings are low. Finally, inspiratory pressure settings on the capillary bed of ⬍ 1 s, gas diffusion is sufficiently
many dedicated NIV systems are referenced to atmosphere, rapid and equilibration of both CO2 and O2 in the alveolus
which can lead to confusion in clinicians more familiar and capillary bed is complete.11-12
with invasive ventilation devices where inspiratory pres- The ultimate PO2 and PCO2 in pulmonary venous blood
sure is referenced to set expiratory pressure (PEEP). entering the left atrium, however, depends not only on V̇A
There are also important advantages to NIV vs invasive and alveolar-capillary gas transport, but also on ventilation
ventilation. By using a noninvasive mask interface instead perfusion matching (V̇/Q̇) relationships throughout the mil-
of an artificial translaryngeal airway, preservation of glot- lions of lung units into which the V̇E distributes.11-13 Factors
tic function may, in fact, reduce aspiration risk from pha- affecting this distribution include regional resistances, com-
ryngeal material. Intermittent breaks from NIV are possi- pliances, functional residual capacities, and the machine-de-
ble, which allows talking and swallowing, and this, coupled livered pressure/flow pattern (square vs decelerating vs vari-
with the absence of an irritating trans-laryngeal airway, may able flow; with or without an inspiratory pause; with or without
improve comfort and reduce sedation needs compared to in- expiratory pressure). In general, positive-pressure breaths will
vasive ventilation.3 NIV can also be helpful in maintaining tend to distribute more to units with high compliance and low
patency of upper-airway obstruction in patients with obstruc- resistance and away from obstructed or stiff units. This cre-
tive sleep apnea and can reduce venous return and pulmonary ates the potential for regional overdistention of healthier lung
edema in selected patients with congestive heart failure.4,5 units in heterogeneous disease states, even in the face of
Importantly, like invasive ventilation, NIV can also injure the normal tidal volumes (see ventilator-induced lung injury dis-
lungs if used inappropriately.6-8 The specific physiologic ef- cussion below). V̇E distribution is also affected by body po-
fects of NIV on both the respiratory system as well as im- sition (eg, gravitational forces tend to distend non-dependent
portant non-respiratory systems (ie, neurologic and cardio- regions) and the presence or absence of inspiratory muscle
vascular) are reviewed below. activity (eg, an actively contracting diaphragm tends to dis-
tribute gas to dependent regions better).14-15
V̇/Q̇ effects are different for CO2 and O2.11,12 Because
NIV Can Augment Minute Ventilation
CO2 is very soluble in blood and CO2 content is essentially
linearly related to PCO2, the ultimate PCO2 in pulmonary ve-
By adding pressure and flow to the mask interface using nous blood is a flow-weighted average of all lung units in
NIV, tidal volumes can be either created during a con- which alveolar gas came into at least some contact with cap-
trolled (ie, machine time-triggered) breath or augmented illary blood (ie, V̇A). On the other hand, the ultimate PO2 in
during assisted (ie, patient effort-triggered) breaths.9 Ei- pulmonary venous blood is not a flow-weighted average but

618 RESPIRATORY CARE • JUNE 2019 VOL 64 NO 6

 PHYSIOLOGIC EFFECTS OF NIV

Arterial pH
7.7 PaCO2
7.6 Alveolar PO2
Arterial pH SaO2
7.5
Alveolar PCO2
7.4
7.3
7.2
7.1
Alveolar PO2 or PCO2 (mm Hg)

130

120

110

100
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90
Arterial CO2 content (volume %)

80

70

60

50

40

30
SaO2 (%)

20

10

0
1 2 3 4 5 6 7 8 9 10 11

Alveolar ventilation (L/min)

Fig. 1. Relationship of alveolar ventilation to alveolar PO2 and PCO2 and to the ultimate SaO2 and PaCO2 with an assumed oxygen consumption
of 250 mL/min and CO2 production of 200 mL/min. The shaded area represents a normal alveolar ventilation. Note that as alveolar
ventilation increases, alveolar PCO2 decreases exponentially, and PaCO2 follows. In contrast, as alveolar ventilation increases, the alveolar
PO2 increases and approaches the inspired PO2. However, because hemoglobin saturation is virtually complete at PO2 values ⬎ 70 –
80 mm Hg, arterial oxygen content rises little at alveolar PO2 above this. Data from Reference 10.

depends heavily on regional V̇/Q̇ matching. This is because NIV Unloads Ventilatory Muscles
O2 is poorly soluble in plasma and because hemoglobin, the
major O2-carrying molecule in blood, is fully saturated when The simplified equation of motion defines the necessary
capillary PO2 values are ⬎ 70 – 80 mm Hg. Under these cir- pressure (Ptot) required to overcome the loads of respira-
cumstances, raising the capillary PO2 has little effect on cap- tory system elastic recoil (Pel) and airway resistance (Rres)
illary blood oxygen content, and thus a lung unit with a high for a given flow (V̇) and volume change (⌬V):
V̇/Q̇ ratio does not have much “extra” oxygen to compensate
for a lung unit with a low V̇/Q̇ ratio. In summary, systemic Ptot ⫽ Pel ⫹ Pres
oxygen content depends heavily on hemoglobin and V̇/Q̇
matching and tends to plateau as V̇E and V̇A are increased Ptot ⫽ (⌬V/CRS) ⫹ (Raw ⫻ V̇)
with NIV. In contrast, systemic arterial CO2 content depends
less on V̇/Q̇ and falls steadily as V̇E and V̇A are increased where CRS is respiratory system compliance, and Raw is
with NIV (see Fig. 1). airway resistance.16

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 PHYSIOLOGIC EFFECTS OF NIV

Individual contributions of inertness and lung tissue re- product is the integral of pressure over inspiratory time.
sistance also impact the equation of motion, but these The pressure-time product, with its reliance on the pres-
contributions are small and are generally disregarded. When sure-time component of loading, better correlates with ven-
present, overcoming intrinsic PEEP contributes to the pres- tilatory muscle energetics and O2 consumption than does
sure requirements to breathe. Note that Ptot is supplied en- work and is thus increasingly used clinically to measure
tirely by the ventilatory muscles (Pmus) during unassisted the energy demands on ventilatory muscles.25-27
breathing. In contrast, during machine-triggered controlled Load tolerance or the load/capacity balance can be ex-
mechanical ventilation, Ptot is supplied entirely by the venti- pressed by a tension-time index (TTmax). The TTmax incor-
lator. During interactive assisted breathing, Ptot is a combi- porates pressure as a fraction of maximum inspiratory pres-
nation of Pmus and machine-applied airway pressure. sure (PImax) and couples this with the fraction of the ventilatory
Although intercostal muscles contribute to Pmus, the most duty cycle devoted to muscle contraction (ie, TI/Ttot)25:
important ventilatory muscle is the diaphragm. This mus-
culotendinous sheet of skeletal muscle separating the tho-
TTmax ⫽ (PI/PImax)(TI/Ttot)
racic and abdominal cavities is the primary muscle of ven-
tilation and is the most used skeletal muscle.17 Although
many of the physiologic principles of skeletal muscle can In a normal subject at rest, TTmax values are generally
⬍ 0.05, and even at high levels of exercise TTmax rarely
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be applied to the diaphragm, including the length–tension

relationship, unique adaptations exist. Compared to limb exceeds 0.1. However, TTmax values ⬎ 0.15 for the dia-
muscles, the diaphragm has a greater proportion of fa- phragm and ⬎ 0.3 for rib cage muscles are related to the
tigue-resistant type I muscle fibers with increased mito- development of ventilatory muscle failure.25
chondrial density, oxidative capacity, and maximal oxy- All of the components of TTmax are likely abnormal in
gen consumption.17,18 These smaller muscle fibers have an patients with respiratory failure due to lung disease. In
increased capillary density that facilitates more efficient patients with high resistive loads (eg, those with COPD,
O2 diffusion, and they have the potential to augment blood asthma, or large airway obstructions) or patients with high
flow up to 4 times more than limb muscles while shifting elastic loads (eg, those with interstitial lung disease, car-
regional blood supplies from other skeletal muscle beds.18 diogenic pulmonary edema, or ARDS), the required in-
Ventilatory muscle capabilities are determined by in- spiratory pressures (PI) can be substantial. The imposed
herent strength and endurance properties, which can be loads from asynchronous patient–ventilator interactions can
profoundly diminished in critically ill patients with meta- also contribute to a need for a high PI. The low PImax in
bolic derangements associated with the systemic inflam- respiratory disease reflects the reduced capabilities of ven-
matory response syndrome.19-21 Capabilities can also be tilatory muscles in the setting of critical illness noted above.
diminished as a consequence of lung hyperinflation liter- Finally, in acute respiratory failure, the higher minute ven-
ally flattening the diaphragm and thereby placing it at a tilation requirement may be associated with an increased
substantial mechanical disadvantage through an unfavor- tidal volume (VT) and shortened Ttot (ie, faster breathing
able length–tension relationship.18 Limitations in energy frequency). This combination can greatly increase TI/Ttot.
supply imposed by hypoperfusion, anemia, hypoxia, mal- Taken together, all of the components of TTmax often change
nutrition, or the inability to extract oxygen, such as that unfavorably in the setting of acute respiratory failure and
seen in sepsis and cyanide poisoning, also predispose to likely contribute to ventilatory muscle failure.
ventilatory muscle failure.22,23 Weak muscles are also less NIV can unload the ventilatory muscles in 2 ways. First,
efficient and require more energy in relation to their max- NIV reduces the number of required patient efforts; second,
imum energy consumption to perform a given task.19 for a given VT, NIV reduces the muscle load during an in-
Ventilatory muscle failure is the loss of the ability of ven- teractive assisted breath (Fig. 2).28 These effects, in turn, can
tilatory muscles to generate the necessary Pmus to provide for reverse fatigue and the reduced neural drive to prevent fa-
the patient’s ventilatory needs. This failure has 2 mecha- tigue. There is controversy surrounding the amount of un-
nisms: one is actual muscle fatigue from muscle overload, loading that is ideal. Clearly total unloading is undesirable
and the other is a reduction in ventilatory drive to protect because it increases the risk for ventilator-induced diaphrag-
muscles from fatigue. Regardless of mechanism, ventilatory matic dysfunction or diaphragm atrophy.29 At the other ex-
muscle failure with its ensuing alveolar hypoventilation and treme, inadequate unloading potentiates muscle failure and
hypercapnia is ultimately related to an imbalance in ventila- may lead to permanent muscle damage.30
tory muscle capabilities versus the loads placed on those A recent concept has been the notion that intermittent (eg,
muscles.22-24 nocturnal) resting of overloaded muscles in patients with
Mechanical loads can be described as a single value for chronic respiratory acidosis may improve muscle function
work or pressure-time product.24 Work is the integral of and lower PaCO2, even during the periods when NIV is not in
pressure over change in volume, and the pressure-time use. The amount of support required to accomplish this is not

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 PHYSIOLOGIC EFFECTS OF NIV

A B C provides adequate gas exchange (ie, a physiologic pH and

a PO2 that fully saturates hemoglobin) with the least amount
of ventilatory muscle loading and air trapping.36 Cortical
inputs (eg, pain, anxiety, stress, artificial airway presence,
and some central nervous system injuries) can also influ-
ence this pattern (loop gain), usually stimulating overall
Volume

D E F ventilatory drive.33,35 In contrast, drugs, such as sedatives

and opioids, and many other central nervous system inju-
ries can depress the overall ventilatory drive. The sleep
state can also modulate these responses.33,35
The ability of NIV to provide adequate gas exchange and
unload muscles can have profound effects on the VCC. Re-
Pressure ducing acidosis and hypoxemia will decrease the intensity
Fig. 2. Pressure-volume plots illustrating loading and unloading and frequency of the VCC output.37 Muscle unloading will
ventilatory muscle with positive-pressure breaths. Pressure is on alter the mechanical inputs into the VCC with variable effects
the horizontal axis, and volume is on the vertical axis. The solid
that often reduce intensity and timing depending upon the
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diagonal line represents the passive respiratory system compli-

ance. Pressures to the left of this line are patient-generated, and types of load (ie, compliance, resistance) being sensed by the
pressures to the right of this line are machine-generated. The area VCC.38 Mechanoreceptors can also sense overventilation and
of the pressure volume plot represents work (shaded for patient overdistention, which often leads to shortening of neural in-
work, open for machine work). A: Represents a normal subject spiratory time and even activation of expiratory muscles.38,39
with normal work. B: Represents a diseased patient with exces-
sive work. C: Represents the same diseased patient being totally
As noted above, nocturnal unloading of chronically over-
unloaded by a machine breath (ie, no patient work). D: Represents loaded muscles may reset the VCC targets for a more normal
the patient only doing enough work to trigger a machine breath PaCO2 and VA during the day.30,31
that provides most of the work to breath. E: Represents the patient Imposed loads from inappropriate NIV settings can
and the ventilator interacting to share the work in a fashion that
also affect the VCC through their effects on muscle
resembles the normal subject work pattern in A. F: Represents a
poorly interactive breath in which inadequate unloading by the loading.33-35,40 Delayed or missed triggers are sensed as
machine produces excessive loading of the patient. Conceptually, an uncomfortable isometric load leading to increased
E would seem ideal. From Reference 41, with permission. effort intensity and pronounced dyspnea.41 If excessive
muscle loading is sensed during flow delivery, this usu-
ally leads to alterations in the spontaneous ventilatory
clear, but some studies suggest that a substantial duration of
pattern to reduce this loading (eg, rapid shallow breath-
high-level NIV (eg, PI ⬎ 20 cm H2O) may be necessary.31,32
In summary, overloading already impaired ventilatory ing) and also is often accompanied by dyspnea.33-34,39
muscles is a major contributor to muscle task failure and Ventilator breath cycling criteria can also impact the
hypercapnia in respiratory disease. Properly applied, syn- VCC.33-35,42-45 A mechanical breath termination shorter than
chronous, assisted NIV is very effective at reducing mus- the neural inspiratory time (machine TI ⬍ neural Ti) can lead
cle loading and facilitating muscle recovery. Moreover, to muscle activity beyond the machine’s flow delivery phase,
some evidence suggests that chronic muscle overloading which can lead to high muscle loading, excessive tidal vol-
can be alleviated by nocturnal use of NIV with improved umes, or triggering of a second breath. In contrast, when
muscle function during the day. mechanical breath cycling terminates after the inspiratory ef-
fort has ended (machine Ti ⬎ neural Ti), dyspnea and expi-
NIV Resets the Ventilatory Control System ratory muscle recruitment may occur in an effort to terminate
the breath. It is also worth noting that, because asynchronous
The ventilatory pattern (tidal volume, frequency, and interactions often results in anxiety and dyspnea, which can
inspiratory/expiratory ratio) is controlled by a collection of stimulate overall ventilatory drive, improving synchrony in
neurons, known as the ventilatory control center (VCC), one area (eg, triggering) can help facilitate achieving syn-
located in the brainstem. The VCC has an inherent respi- chrony in other areas (eg, flow demand).44,45
ratory rhythm generator that interacts with several inputs. In summary, NIV can affect the VCC in a variety of ways.
Two important inputs come from chemoreceptors (ie, PO2, Improving gas exchange, reducing muscle loads, and reduc-
PCO2, and pH receptors) located in the great vessels and the ing dyspnea can all result in a more normal ventilatory pat-
fourth ventricle of the brain, and from mechanoreceptors tern. Importantly, central nervous system abnormalities can
(ie, stretch and irritant receptors) in the thorax and venti- complicate this scenario, and a poor setup of NIV with sig-
latory muscles (Fig. 3).33-35 The optimum ventilatory pat- nificant imposed loading may provoke VCC responses that
tern generated by a normal VCC is generally the one that serve only to worsen the situation.

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 PHYSIOLOGIC EFFECTS OF NIV

NIV improves gas exchange Oxygenation

NIV unloads muscles
Respiratoy muscle loads
pH (CRS, Raw, volume/stretch)

Affects intensity
Affects intensity
Affects intensity and timing

Intrinsic pattern generator NIV reduces dyspnea

in brainstem

Neurologic structural and

Loop gain
functional integrity
(including drugs/sleep)

Effort intensity; effort timing

Fig. 3. Noninvasive ventilation (NIV) has effects on the ventilatory control center (VCC) in the brainstem. The VCC has an intrinsic pattern
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generator with important inputs from gas exchange sensors and from mechanical load sensors. The output from the VCC controls
ventilatory muscle inspiratory muscle intensity and timing. Importantly, this output can be modulated by cortical influences and drugs, an
effect sometimes referred to as a loop gain. Positive-pressure NIV can affect the VCC in a variety of ways that include beneficial (and
sometimes harmful) effects on gas exchange, ventilatory muscle loading, and even cortical influences that are affected by the sense of
dyspnea/anxiety. CRS ⫽ compliance of the respiratory system; Raw ⫽ airway resistance.

Alveolar Recruitment and Gas Exchange PEEP, however, can also be detrimental. Because the tidal
breath is delivered on top of the baseline PEEP, end-inspira-
Parenchymal lung injury produces V̇/Q̇ mismatching tory pressures are usually raised by PEEP application (al-
and shunts because of alveolar inflammation, flooding, though this increase may be less than the actual increased
and collapse.46-48 In many of these disease processes PEEP level because of PEEP-induced improved compliance).
(but not all), substantial numbers of collapsed/atelec- This increase must be considered if the lung is at risk
tatic alveoli can be recruited during the NIV-delivered for regional overdistention. Moreover, because paren-
VT. Additional recruitment can sometimes be provided chymal lung injury is often quite heterogeneous, appro-
with the use of formal recruitment maneuvers, although priate PEEP in one region may be suboptimal in another
this is much more commonly done with invasive ven- and yet excessive in another.48,53,54 Optimizing PEEP is
tilation than during NIV. thus a balance between recruiting the recruitable alveoli
Once alveoli are recruited, PEEP can be applied during in diseased regions without over-distending previously
NIV to prevent de-recruitment. PEEP is generally pro- recruited alveoli in healthier regions. Another potential
duced by expiratory circuit valves or by continuous flow detrimental effect of PEEP is that it raises mean in-
provided during the expiratory phase (applied PEEP). PEEP trathoracic pressure, which can compromise cardiac fill-
can also be produced as a consequence of short expiratory ing in susceptible patients (see below).
times in lung units with long expiratory time constants
(intrinsic or auto-PEEP in highly compliant, highly ob- Other Physiologic Effects of NIV: Intended and
structed lung units).49,50 Importantly, applied PEEP is gen- Unintended
erally distributed uniformly throughout the lungs, whereas
intrinsic/auto-PEEP predominantly develops in lung units
Maintaining Upper-Airway Patency
that may need it the least (eg, emphysematous or severely
obstructed lung units).51
Alveoli prevented from de-recruiting by PEEP provide A common indication for NIV (either with PEEP or as
several potential benefits. First, recruited alveoli improve simple CPAP) is for managing upper-airway collapse in pa-
V̇/Q̇ matching and gas exchange throughout the ventila- tients with obstructive sleep apnea. The underlying physio-
tory cycle.47 Second, patent alveoli throughout the venti- logic principle is that the positive upper-airway pressure lit-
latory cycle are not exposed to the risk of injury from the erally splints open the collapsed upper-airway structures
shear stress of repeated opening and closing.46-48 Third, during sleep.4 Often only simple CPAP is required, although
PEEP prevents surfactant breakdown in collapsing alveoli some patients do better with the addition of inspiratory pos-
and thus improves lung compliance.52 itive pressure.

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 PHYSIOLOGIC EFFECTS OF NIV

Reducing Imposed Triggering Loads From (pneumopericardium), subcutaneous tissue (subcutaneous

Auto-PEEP emphysema), pleura (pneumothorax), and vasculature (air
emboli).63 The risk for extra-alveolar air increases as a
The PEEP applied with NIV can also help with assisted function of the magnitude and duration of alveolar over-
breath triggering in patients with a significant triggering distention. Thus, interactions of respiratory system me-
load imposed by auto-PEEP.55-57 In this setting, patients chanics and mechanical ventilation strategies (eg, high re-
must first decrease alveolar pressure below the auto-PEEP gional VT and PEEP, both applied and intrinsic) that
level before mask pressures will fall to trigger the assisted produce regions of excessive alveolar stretch (ie, transpul-
breath. This can be an intolerable isometric-like load on monary distending pressures in excess of 40⫹ cm H2O)
inspiratory muscles leading to respiratory failure. By pro- for prolonged periods create alveolar units at risk for rup-
viding applied PEEP below the auto-PEEP level, the gra- ture.
dient between alveolar pressure and mask pressure is re- A parenchymal lung injury not associated with extra-
duced, thereby reducing the imposed triggering load. alveolar air can be produced at lower transpulmonary pres-
sures in the setting of excessive maximal lung stretch (ie,
Cardiac Interactions: Both Beneficial and Harmful end-inspiratory transpulmonary pressures exceeding phys-
iologic maximums), excessive tidal lung stretch (ie, VTs
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Application of elevated intrathoracic pressure from NIV exceeding the physiologic range), or collapse-reopening of
can have profound effects on cardiovascular function.5,58-61 injured alveoli.6-8,64 Frequency of stretch, acceleration of
In general, as mean intrathoracic pressure is increased, stretch, and vascular pressures may also be involved. These
venous return is decreased and cardiac output/pulmonary forms of ventilator-induced lung injury manifest patholog-
perfusion consequently decreases. This may be com- ically as diffuse alveolar damage6,8,64 and are associated
pounded by increased right ventricular afterload. Of note, with cytokine release65,66 and bacterial translocation.67
however, increased intrathoracic pressures may also result The risk of ventilator-induced lung injury can be re-
in better left ventricular function due to an effective re- duced during NIV with the use of lung-protective settings:
duction in left ventricular afterload.5,61 Thus, in patients transpulmonary end-inspiratory pressures ⬍ 30 cm H2O,
with left heart failure, elevated intrathoracic pressure may tidal volumes ⬍ 8 mL/kg ideal body weight (or perhaps
actually improve cardiac function, and intrathoracic pres- VT driving pressures ⬍ 15 cm H2O), and judicious use of
sure removal may produce weaning failure.61 PEEP balancing end-inspiratory distending pressures and
Intrathoracic pressures can also influence distribution of FIO2 to meet a PaO2 target.68,69 A clinical challenge with
perfusion. The relationship of alveolar pressures to perfu- NIV (and invasive ventilation) occurs when ventilator set-
sion pressures in the West three-zone lung model help tings are minimal, yet a vigorous patient effort results in
explain this.11,12,62 Specifically, the supine human lung is potentially harmful transpulmonary pressures and vol-
generally in a zone 3 state (ie, permanently distended cap- umes.70 Under these circumstances, of course, reversible
illaries with low and normal V̇/Q̇ units). As intra-alveolar causes of a vigorous inspiratory effort (eg, pain, acidosis,
pressures rise, however, zone 2 (ie, intermittently distended anxiety) must be addressed. Beyond that, however, man-
capillaries and high V̇/Q̇ units) and zone 1 (ie, collapsed agement of such patients without obvious causes is prob-
capillaries and dead space) regions can appear. lematic.70,71 Some argue that an inappropriate excessive
Positive-pressure mechanical ventilation can affect other respiratory drive should be blunted with sedatives or opi-
aspects of cardiovascular function. Specifically, dyspnea, anx- oids to prevent self-induced lung injury. Others counter
iety, and discomfort from inadequate NIV support can lead to that self-induced lung injury is a controversial concept and
stress-related catechol release with subsequent increases in that the use of sedating drugs should be avoided to facil-
myocardial oxygen demands and risk of dysrhythmias.5,58-61 itate the ventilator withdrawal process.
In addition, coronary blood vessel oxygen delivery can be
compromised by inadequate gas exchange from the lung in- Production of Auto-PEEP
jury coupled with low mixed venous PO2 due to high oxygen
consumption demands by the inspiratory muscles. High levels of V̇E from NIV support can lead to the
development of auto-PEEP, especially in patients with in-
Ventilator-Induced Lung Injury adequate expiratory times or lung units with excessively
long expiratory time constants.72 If pressure-controlled NIV
The lung can be injured when it is stretched excessively is being used, auto-PEEP results in progressively smaller
by positive-pressure ventilation, whether applied either in- VT delivery; if volume-controlled NIV is being used, this
vasively or noninvasively. The most well recognized in- results in the buildup of high inspiratory pressures.55
jury is that of alveolar rupture presenting as extra-alveolar The development of auto-PEEP can be particularly prob-
air in the mediastinum (pneumomediastinum), pericardium lematic in patients with severe obstruction who are receiv-

RESPIRATORY CARE • JUNE 2019 VOL 64 NO 6 623

 PHYSIOLOGIC EFFECTS OF NIV

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69. Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, 72. Laghi F, Segal J, Choe WK, Tobin MJ. Effect of imposed inflation
Schoenfeld DA, et al. Driving pressure and survival in the acute time on respiratory frequency and hyperinflation in patients with
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755. 2001;163(6):1365-1370.
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71. Brochard L. Ventilation-induced lung injury exists in spontaneously latory support. Am Rev Respir Dis 1992;145(1):114-120.
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Discussion spiratory effort is a very complicated Davies: How many times have you
issue, and it’s one that is grossly un- approached a resident or even a fel-
Davies: Neil [MacIntyre], you re- derappreciated because, in the absence low to let them know a patient ap-
ferred to the fact that patient effort of obvious discomfort, it can be hard pears uncomfortable, and their imme-
can have an unintended consequence to appreciate from simple patient ob- diate response is to treat the numbers?
of adding to the transpulmonary pres- servation. You also may not appreci- That is, “The patient must be okay
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sure, and I think of some of the pa- ate it from circuit measurements, and since his numbers are okay.” It’s ex-
tients I see on NIV who really seem to these vigorous patient efforts may be actly what you were saying: the fail-
be struggling. In the battle of trying to generating potentially dangerous lev- ure to recognize that something bad is
provide lung-protective ventilation, I els of transpulmonary pressures and going on. We just can’t show what it
do wonder about transpulmonary pres- creating regional overdistention even is other than by clinical assessment.
sure, especially in some of those pa- though VT, the global total volume, is
tients who have a high respiratory not excessive. I assume you’ll talk MacIntyre: Let me give you a clin-
drive. about this Bhushan [Katira]—I hope ical scenario. You have a COPD pa-
I’m not contradicting you. tient who’s getting better, who has
MacIntyre: I didn’t have time to go been weaned down to 5 cm H2O of
into it, but thank you for bringing that Katira: Yes, I will talk about this, pressure support, but you don’t want
up. Especially in the setting of asyn- and you are not contradicting me at all. to take the tube out yet because secre-
chrony, where patients are struggling
tions are still a concern and the patient
to trigger and/or get more flow or lon- Kacmarek: I just think it’s a gen-
is not as awake as you’d like. Despite
ger durations of flow, you may have eral concern with any patient who is
providing only 5 cm H2O of pressure
only have a small pressure applied by breathing spontaneously and is being
support, the patient looks comfortable
the machine. However, if you were to mechanically ventilated, whether it’s
but the VT is 11 mL/kg. There’s no
look in the pleural space with an esoph- NIV or invasive. We have a false sense
clear right answer here—I’m just cu-
ageal balloon or other technology, you of security if the patient’s gas exchange
may see enormous pressure swings is reasonable, and we commonly fail rious what the experts here might do.
taking place. It may appear from pa- to appreciate the amount of effort that Would you reach for the dexmedeto-
tient observation that the lung is not patients are putting forth. Even with midine and say we need to blunt this
excessively inflating, so maybe it’s not good gas exchange, if patients look drive, or would you leave everything
a big deal. Well, the problem is that like they’re using every accessory alone? Blood gases are OK, there is no
it’s a regional phenomenon, and yes, muscle they have, the decision to pro- metabolic acidosis, there is no sign of pain.
maybe your global VT is not huge, but vide controlled ventilatory support is So how many would reach for a drug,
these huge pressure swings have the not made when it should be made. We pick whichever one you like, to blunt that
potential to pull gas into the healthier do a lot of patients a disservice by 11 mL/kg VT? [Pause for panel response,
lung units and cause a regional over- allowing them, when they look un- during which no one raised a hand].
distention injury. Yoshida and col- comfortable, to continue to ventilate
leagues1 have shown that this high in- that way instead of providing control Kacmarek: Not as the first choice.
spiratory effort in the setting of bad of ventilatory support. Because we’re
mechanics or poor flow delivery can not going to know the transpulmonary MacIntyre: Alright, you do all the
create a pendelluft effect. You can lit- pressure, since we do not put esoph- things that Bob [Kacmarek] wants you
erally suck gas out of one region of ageal balloons in every patient, and to do to make the ventilator better, and
the lung and overinflate another re- we do not have electrical impedance still same scenario. [Pause for panel re-
gion even without delivering a VT at tomography available, our clinical sponse; still no hands raised]. Every-
all. The idea of aggressive patient in- judgment must guide us. body would let them ride? Interesting.

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* Hess: I think the important question MacIntyre: Maybe COPD was a bad increased with use of large VTs, even
is why is this patient desiring a VT of example, and in fact I see this more in though the lungs are near normal and
11 mL/kg? Is the patient acidotic, is the the neurologic unit than I do in my med- end-inspiratory distending pressures are
patient in pain, is the patient anxious? ical ICU. So if I gave you a neurologic not excessive. Some fascinating animal
patient, would that change your mind? data going back 30 years demonstrated
MacIntyre: I already stated that there that modest hyperventilation for 72 h
was no obvious cause—no pain, no ac- Hill: No. with end-inspiratory volumes well be-
idosis. You are messing up my survey! low total lung capacity created tremen-
MacIntyre: I still can’t get anybody dous lung injury.2 I don’t know who
Kacmarek: It’s not a good survey! to sedate this patient! By the way, based these athletes are who go 48 h with high
on what I know about the trade-offs of VT ventilation—that’s impressive.
* Hess: It’s not so black and white. sedation versus the potential for SILI, I There are marathon and triathletes who
would not sedate under these conditions I know will go 6 – 8 h.
MacIntyre: Rarely is clinical man- either.
agement black or white, and I agree Hill: We did some studies on Iron
with you there are many things that Benditt: I deal with a lot of spinal Man triathletes. We enrolled about
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must be assessed in making clinical cord-injured patients and because of 40 subjects—this was before institu-
decisions. But there are patients, and I interruption of baroreflexes and per- tional review boards were as stringent.
think if you’re honest with yourself haps other physiologic abnormalities, We published an article in one of the
you’ve seen them—I know I’ve seen they often desire a much higher VT—in sports journals.3 They had a slight re-
them. They look pretty darn good, fact, it can be really big on occasion. duction in VT, and people think they
they’re comfortable, so why are they I’ve done many things to try to re-
may get a bit of edema, but these guys
demanding such high VT? There’s this verse that without any effect; I have
were going anywhere from 8 –16 h and
notion that, in the systemic inflamma- had spinal cord-injured patients who
they were fine. The VTs during the
tory response syndrome, you get brain have been on 15 mL/kg for years
event were at least double or more of
dysfunction that alters that loop gain I with no effects. It makes me wonder
what they would breathe at rest.
mentioned earlier to the point where whether we should do a survey of
there is a demand for a higher VT. The spinal cord-injured patients because
Kacmarek: The data that are out
neurologic patients do this all the many of them show these large VTs.
there show the type of injury you’re talk-
time—there is this drive for a bigger ing about occurs in the hypoxemic re-
than normal VT. This invokes this no- Hill: It’s not just spinal cord-in-
jured patients either, it’s also chronic spiratory failure patient, and I think that’s
tion of self-induced lung injury (SILI), the patient we’re all concerned with.
which I think is a very reasonable con- neuromuscular disease patients. I’ve
had some over the years who like Every one of us sees this type of
cept. Dean [Hess] and Bob, you’re ab-
large VTs and they’re ventilated patient; if we cannot correct the ven-
solutely right, of course you go through
at ⬎10 mL/kg for years. Endurance tilatory pattern in any other way, we
a checklist: why would this patient be
athletes will ventilate themselves would sedate that patient. Or, if it is
demanding such a large VT? But once
with high VTs sometimes for a noninvasively ventilated patient,
you’ve gone through a checklist, there
24 – 48 h depending on what crazy we would elect to intubate that pa-
are patients who remain who just seem
thing they’re doing, and they don’t tient. But the animal data are pretty
to like a big VT. And what do we do
get any significant lung injury. I think much from ARDS models.
with them?
when you have a vulnerable lung, if
you have acute lung injury, then MacIntyre: Mascheroni’s were nor-
Hill: One of the reasons my hand
you’re at risk if you ventilate at mal sheep.2
didn’t go up is you gave us a COPD
patient, and if you gave us somebody higher lung volumes. But I think pa-
tients who don’t have acute lung in- Kacmarek: Kolobow’s were nor-
with hypoxemic respiratory failure I
jury are not necessarily at high risk. mal sheep but affected their central
might have made a choice. But I don’t
nervous system.4
see 11 mL/kg too often in COPD pa-
tients who are on a ventilator. MacIntyre: I accept all the points
everyone has made, but there is litera- MacIntyre: But he did get a whop-
ture out there that self-induced lung in- ping lung injury. And again I go back
jury is real. The postoperative arena is, to the postoperative patient who does
* Dean R Hess PhD RRT FAARC, Managing I think, an interesting one, where post- have normal lungs and is at higher risk
Editor, RESPIRATORY CARE. operative pulmonary complications are for postoperative complications.

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 PHYSIOLOGIC EFFECTS OF NIV

* Hess: Back to Nick’s [Hill] point, Hill: The Operation Everest II study,7 oxygen concentrator companies,
I believe there was a study a number of which was a simulated ascent of Ever- OECO (Oxygen Enrichment Com-
years ago where the authors took elite est in an Army research decompression pany, Schenectady, NY), would rou-
athletes and exercised them to the max- chamber about 5 miles from where I tinely treat racehorses by connect-
imum of whatever they could do and live, had previously healthy, relatively ing them to that device through a
then they did bronchoalveolar lavage.5 athletic young men go through a 40-d nasal catheter. The key attribute of
There were red cells in the bronchoal- simulated ascent to the summit of Ever- the OECO device was it only pro-
veolar lavage suggesting there was in- est where they put them on exercise vided 30% oxygen but it provided
jury, either on the vascular side or on bikes. Do you know what their minute 100% relative humidity at a very high
the lung side, or both, which to me sug- volume was at the summit of Everest? flow. It may actually be the first high-
gests there was some injury there. It was 180 L/min on average to drive flow nasal cannula ever used.
the CO2 down so they could oxygenate,
Hill: That’s different than the en- and they sustained that, not necessarily
durance situation; you’re going to an at the full 180 L/min, but certainly at REFERENCES
extreme level of exertion. It’s sort of extremely high volumes and frequen-
like a thoroughbred horse. cies for probably at least a couple of 1. Yoshida T, Roldan R, Beraldo MA, Torsani
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weeks at higher altitudes. V, Gomes S, De Santis RR, et al. Spontaneous

* Hess: That has blood in its spu- effort during mechanical ventilation: maximal
tum at the end of a race. MacIntyre: I had the privilege of go- injury with less positive end-expiratory pres-
ing to Nepal earlier this year, and I was sure. Crit Care Med 2016;44(8):e678-e688.
2. Mascheroni D, Kolobow T, Fumagalli R,
Hill: Right, you give racehorses a di- fascinated with the Everest phenomena.
Moretti MP, Chen V, Buckhold D. Acute
uretic like furosemide beforehand, it re- I did not climb Everest (no surprise respiratory failure following pharmacologi-
duces the hemoptysis. If you stretch the there!), but I did tour in a helicopter and cally induced hyperventilation: an experi-
lung enough and increase pulmonary ar- was especially intrigued with the Ever- mental animal study. Intensive Care Med
tery pressures enough, it’s going to be est basecamp situated around 17,500 ft 1988;15(1):8-14.
injured. I think it’s a matter of degree; if above sea level. Climbers use the base 3. Hill NS, Jacoby C, Farber HW. Effect of an
you’re not at that level of extreme ex- camp as a place to adapt to hypoxemia, endurance triathlon on pulmonary function.
Med Sci Sports Exer 1991;23:1260-1264.
ertion, I think the normal human lung a process that takes several weeks and
4. Kolobow T, Moretti MP, Fumagalli R,
can endure much higher tidal volumes involves multiple mechanisms affecting Mascheroni D, Prato P, Chen V, Joris M.
than we target in the ICU for hypox- hemoglobin and cellular metabolism. Severe impairment in lung function induced
emic respiratory failure patients. But perhaps it’s also a place to adapt to by high peak airway pressure during me-
hyperventilation and the stretch injury chanical ventilation. An experimental study.
MacIntyre: Xiaofei Cong at Mayo that might occur otherwise. It took 40 d Am Rev Respir Dis. 1987;135(2):312-315.
has done some interesting work6 that to reach the summit in that simulated 5. Hopkins SR, Schoene RB, Henderson WR,
Spragg RG, Martin TR, West JB. Intense ex-
may address this question. He showed model, and maybe that’s long enough
ercise impairs the integrity of the pulmonary
that if you took the lungs slowly over to create some adaptation to not only blood-gas barrier in elite athletes. Am J Respir
time to a larger volume, it adapted to hypoxemia but hyperventilation. Crit Care Med 1997;155(3):1090-1094.
those larger volumes. So it’s conceiv- 6. Cong X, Hubmayr RD, Li C, Zhao X. Plasma
able that in these long-term neurologic † Branson: Sometimes these dis- membrane wounding and repair in pulmo-
patients they actually might adapt to a cussions trigger old memories. There nary diseases. Am J Physiol Lung Cell Mol
Physiol 2017;312(3):L371-L391.
larger VT and it’s this stretching phe- was a time when one of the original
7. Sutton JR, Reeves JT, Wagner PD,
nomenon over time that allows it to go Groves BM, Cymerman A, Malconian MK, et
on. And that would not occur, or would al. Operation Everest II: oxygen transport dur-
be less likely to occur, in the acute set- † Richard D Branson MSc RRT FAARC, Edi- ing exercise at extreme simulated altitude.
ting. tor in Chief, RESPIRATORY CARE. J Appl Physiol 1988;64(4):1309-1321.

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