Spontaneous Breathing During Mechanical

Ventilation: A Two-Edged Sword*

Neil MacIntyre, MD from repetitive opening-closing. Second, there is also a tearing
Division of Pulmonary and Critical Care Medicine phenomenon at the interface of lung units being recruited and de-
Duke University Medical Center recruited adjacent to lung units that do not open at all. Preventing
Durham, NC these phenomena is one of the rationales for the use of PEEP to
maintain alveolar recruitment throughout the ventilator cycle.

M
odern mechanical ventilators are equipped with the What this current study shows is that in the setting of sub-
capability to sense patient effort and respond to this optimal PEEP and the presence of collapsed but recruitable
effort by delivering either a set flow or a set pressure. lung units, a spontaneous effort, instead of moving gas into the
There are several advantages to allowing spontaneous breaths lungs, creates a pendelluft effect and moves gas from already
during mechanical ventilation (1). First, among them, is that open units into the underrecruited units. It is interesting that
the need for sedation is often minimized in patients who are this pendelluft effect actually improves gas exchange, even
allowed to make spontaneous efforts. This may impact dura- though it exposes alveoli to injurious collapse-reopening strain.
tion of mechanical ventilation. Second, the movement of the These conflicting effects reminds one of the National Insti-
entire diaphragm with spontaneous effort tends to distribute tutes of Health (NIH) Acute Respiratory Distress Syndrome
gas more evenly in the lung. This may enhance the recruit- (ARDS) Network trial comparing a small tidal volume strategy
ment and ventilation of dependent regions of the lung, thereby to a large tidal volume strategy (7). In that study, over the first
improving ventilation perfusion matching and reducing ven- 2–3 days of the trial, the large tidal volume group actually had
tilator-induced lung injury from alveolar collapse-reopening better gas exchange and respiratory system mechanics even
phenomenon (2). Third, allowing the diaphragm to contract though they went on to suffer an increased mortality. This is
forestalls the development of muscle atrophy, a phenomenon a reminder that sometimes transiently improved physiology
that can develop quickly and has been termed “ventilator- may be occurring at an excessive price—in the NIH ARDS
induced diaphragmatic dysfunction” (3). Network case overdistention of healthier units eventually led
Spontaneous efforts, however, may have adverse effects. to later development of lung injury.
Spontaneous efforts generate negative pleural pressure and At the end of the day, clinicians are constantly faced with
this adds to the transpulmonary pressure, the actual stretch- the decision as to whether to allow spontaneous effort during
ing pressure across the lungs. This can sometimes confuse cli- mechanical ventilation. As noted above, spontaneous efforts
nicians when they fail to recognize that the measured airway are a two-edged sword. They can not only offer advantages of
pressure is only one component of transpulmonary pressure. comfort, ventilation distribution, and ventilator muscle func-
Furthermore, in the setting of high spontaneous inspiratory tion but also cause harm from overstretching. Furthermore, as
demands from such things as anxiety, fever, pain, agitation, this current study shows, in the presence of suboptimal PEEP,
acidosis, and the like, pressure targeted ventilation may result a pendelluft effect not only may improve gas exchange but also
in unwanted large tidal volumes and excessive transpulmonary can worsen lung injury. Clinicians need to take all these con-
pressures. Indeed, it may be for these reasons that a neuromus- siderations into account when deciding whether to allow spon-
cular blockade may be of utility in early respiratory failure (4). taneous efforts during mechanical ventilation. Furthermore,
Yoshida et al (5) in Japan and Brazil have demonstrated in clinicians must assure that if spontaneous efforts are occur-
this issue of Critical Care Medicine and in an earlier publication ring, appropriate PEEP is present.
in the American Journal of Respiratory and Care Critical Medicine
(6) that spontaneous efforts may produce an additional injury if
suboptimal positive end-expiratory pressure (PEEP) is present. REFERENCES
1. Gilstrap D, MacIntyre N: Patient-ventilator interactions. Implications
The concept is an interesting one. Specifically, it is well known for clinical management. Am J Respir Crit Care Med 2013;
that collapsed alveoli that are repeatedly recruited with a tidal 188:1058–10688
breath are prone to injury (2). The mechanism of injury is prob- 2. Protti A, Andreis DT, Monti M, et al: Lung stress and strain during
ably two-fold. First, there is a direct injury to alveolar structures mechanical ventilation: Any difference between statics and dynam-
ics? Crit Care Med 2013; 41:1046–1055
3. Petrof BJ, Hussain SN: Ventilator-induced diaphragmatic dysfunc-
*See also p. e678. tion: What have we learned? Curr Opin Crit Care 2016; 22:
67–72
Key Words: mechanical ventilation; pendelluft; spontaneous breathing
4. Hraiech S, Forel JM, Papazian L: The role of neuromuscular
Dr. MacIntyre received funding from Breathe Technology, Inspirx, and blockers in ARDS: Benefits and risks. Curr Opin Crit Care
Medtronics. 2012;18:495–502
Copyright © 2016 by the Society of Critical Care Medicine and Wolters 5. Yoshida T, Roldan R, Beraldo MA, et al: Spontaneous Effort During
Kluwer Health, Inc. All Rights Reserved. Mechanical Ventilation: Maximal Injury With Less Positive End-
DOI: 10.1097/CCM.0000000000001765 Expiratory Pressure. Crit Care Med 2016; 44:e678–e688

Critical Care Medicine www.ccmjournal.org 1625

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Editorials

6. Yoshida T, Torsani V, Gomes S, et al: Spontaneous effort causes 7. NIH ARDS Network: Ventilation with lower tidal volumes as
occult pendelluft during mechanical ventilation. Am J Respir Crit Care compared to traditional tidal volumes in acute lung injury and acute
Med 2013; 188:1420–1427 respiratory distress syndrome. N Engl J Med 2000;342:1301–1308

Sepsis-Induced Endoplasmic Reticulum Stress:

A Matter of Life and Death?*
Elliott D. Crouser, MD PKR-like endoplasmic reticulum kinase, inosol-requiring
Division of Pulmonary, Allergy, Critical Care, and Sleep enzyme 1α (IRE1), activating transcription factor-6 (ATF6).
Medicine Each of these receptors promotes the transcription of genes
The Ohio State University Wexner Medical Center that encode multiple proteins, comprising the “unfolded
Columbus, OH protein response” (UPR). The UPR leads to altered cell
metabolism, promotes excessive oxidant formation

D
espite advances in resuscitative care, including sepsis (e.g., mitochondrial) and proinflammatory immune responses,
treatment “bundles” designed to optimize the timing and ultimately controls the fate of the cell (e.g., programmed
of antibiotics and fluid resuscitation, sepsis-related cell death or apoptosis) (5). The ER stress response can be
organ failures remain a leading cause of in-hospital death (1). viewed as a “tipping point” at which the cell’s capacity to main-
When confronted with a pathogenic organism the human tain normal function and/or viability is compromised, while
host typically mounts an intense, localized immune response triggering the production of danger signals capable of promot-
to eradicate the threat. However, when the inoculum is very ing regional and systemic inflammation.
large or if the host’s immune response is impaired, the patho- In this issue of Critical Care Medicine, Liu et al (6) hypoth-
gen may get the upper hand, leading to dissemination of the esized that an inhibitor of ER stress, 4-phenylbutyric acid
infection and, in turn, a systemic inflammatory response from (PBA), would suppress inflammation, reduce organ dam-
the host. Through multiple poorly understood mechanisms, age, and promote survival in the setting of severe sepsis. To
sepsis leads to altered function of vital organs, characterized this end, a rat cecal-ligation and puncture (CLP) model was
clinically by the need for “life support” in the form of vaso- used to establish “septic shock” (i.e., as defined by hypotension
pressor agents, ventilators, and renal replacement therapies. within 12 hr) and signs of organ damage. To replicate the delay
Failure to recover from sepsis-induced multiple organ failure in sepsis treatment that is typical of the human condition,
(e.g., withdrawal of life support) is the most common cause of PBA was administered 12 hours after the onset of sepsis in one
death in medical ICUs (2, 3). Unfortunately, no single proin- group of animals, and this group was compared with untreated
flammatory cell receptor, signaling pathway, or inflammatory controls and to a group treated with PBA immediately after
molecule target are shown to be essential for the pathogenesis induction of sepsis. Advantages of using rats for this study,
of sepsis-induced organ failures, such that conventional phar- compared with the more commonly used murine CLP model,
macological manipulations of specific molecular targets have include the ability to analyze an array of vital organ function
been uniformly ineffective. and injury parameters in each animal due to their larger size,
Endoplasmic reticulum (ER) stress refers to a complex, and rats are closer to humans in terms of the physiological
highly regulated intracellular response to conditions that responses to environmental challenges (7). The protocol fur-
lead to altered protein formation. ER stress can be triggered ther included measurement of a number of byproducts of ER
by any number of critical illnesses, including ischemia-reper- stress, including tissue-specific release of C/EBP homologous
fusion injury, inflammation, and other conditions associ- protein (CHOP), IRE1, ATF6; and systemic release of biomark-
ated with excessive reactive oxygen species formation (4, 5). ers of oxidant stress (reactive oxidant species) and inflamma-
The latter leads to excessive disulfide bond formation tion (tumor necrosis factor-α, interleukin (IL)-6, and IL-10).
within newly formed proteins in the golgi apparatus and The results of the study by Liu et al (6) convincingly dem-
ER, which are detected by transmembrane ER receptors onstrate a time-dependent benefit of PBA treatment for severe
sepsis. A significant advantage of the rat model was the ability
to monitor numerous hemodynamic indices, organ-specific
biomarkers, metabolic and inflammatory variables, as is com-
*See also p. e689.
monly performed during human sepsis. In so doing, the study
Key Words: endoplasmic reticulum stress; phenylbutyric acid; sepsis
unequivocally shows benefits of PBA treatment in the setting
Dr. Crouser disclosed other support (National Institutes of Health;
Beckman Coulter; and Mallinckrodt Pharmaceutical). of untreated septic shock (no antibiotics, limited volume resus-
Copyright © 2016 by the Society of Critical Care Medicine and Wolters citation) when measured in terms of attenuating circulatory
Kluwer Health, Inc. All Rights Reserved. collapse, reducing organ damage and indices of ER stress, and
DOI: 10.1097/CCM.0000000000001694 improving short-term mortality during septic shock. Related

1626 www.ccmjournal.org August 2016 • Volume 44 • Number 8

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.