J Appl Physiol 118: 1553–1556, 2015;
doi:10.1152/japplphysiol.01013.2014.
Perspectives
VIEWPOINT
Precedence and autocracy in breathing control
Philippe Haouzi
Pennsylvania State University, College of Medicine, Department of Medicine, Division of Pulmonary and Critical Care
Medicine, Hershey, Pennsylvania
Address for reprint requests and other correspondence: P. Haouzi, Dept. of
Medicine, Division of Pulmonary and Critical Care Medicine, Pennsylvania
State Univ., College of Medicine, 500 Univ. Drive, H041, Hershey, PA 17033
(e-mail: [email protected]).
http://www.jappl.org
system (RCS). This paper presents the view that two fundamental properties of the RCS must be considered to
account for the behavior of breathing control at rest, during
exercise, as well as in some very unusual conditions,
wherein circulation is altered.
The first property is the ability of the RCS to select among
various inputs, some of them taking precedence over others, in
elaborating the ventilatory outcome. This behavior cannot be
anticipated or predicated from the behavior of individual receptors. This strategy is well illustrated by the effects of the
temporal dissociation of various stimuli to breathe operating
otherwise at the same time (19). For instance, the control (13)
and the effects of moving limbs on muscle receptors (24) have
very different kinetics from the change in gas exchange (42)
(very rapid for the former, much slower for the latter). When
imposing fast vs. slow up-and-down variations in work rate
changes during exercise (3, 44), breathing appears to “follow”
the slow change in metabolism/pulmonary gas exchange and to
ignore the effects of the motor activity as well as corollary
signals originating from the structures controlling muscle contractions or locomotion (19). Yet signals related to the control
of muscle locomotion as well as those resulting from contractions (intensity or frequency) do stimulate ventilation (5, 9).
The respiratory control system, when engaged in exercise,
appears, therefore, to select a strategy, which constrains ventilation to follow information that prevent PaCO2 from rising,
disregarding in the process other powerful sources of breathing
stimuli, even if they are much faster.
The second feature can be described as an autocratic
behavior of the respiratory control system: the respiratory
neurons appear to be able to maintain their ongoing level of
activity (whether low, high, or periodic) regardless of the
signals or conditions that have triggered or maintained this
activity. This property is best exemplified by the observation
that the generation of normal breath cycles is maintained
during the initial period of a cardiac arrest (CA) in the
sheep, despite the absence of pulmonary or systemic blood
flow (20). Similarly, breathing is maintained unchanged in
humans, in conscious sedation, during and after a 10- to 15-s
period of experimental fibrillation-induced CA and the ensuing phase of low blood pressure leading to blow flow
restoration while testing implantable defibrillators (20). In
addition, during ventricular fibrillation-induced CA at the
cessation of muscle contractions in sheep (23), minute
ventilation persists at the same level and with the same
pattern as during the period of exercise (Fig. 1), notwithstanding the cessation of the contractions. Consequently,
because breathing is higher during contractions than at rest,
minute ventilation was therefore maintained at much higher
levels (up to 50 l/min) during the recovery from exercise
8750-7587/15 Copyright © 2015 the American Physiological Society
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THE MEANDERING PATHS FOLLOWED by the evolutionary pressure
produced by chance and necessity (32) have shaped the
structures and functions of the respiratory control system
through the slow process of natural selection (7, 8, 35). The
resulting complexity of the respiratory control system has
made it difficult to decipher the intricate laws or properties
behind the mechanisms controlling the rhythmic activity of
the respiratory muscles in humans. This contention does not
pertain so much to our understanding of the functions of the
specific receptors (chemoreceptors, pulmonary, cardiac,
muscle, laryngeal stimuli, etc.) or of the medullary or
supramedullary structures involved in breathing. Rather
what is still lacking is a comprehensive and meaningful
frame of reference making intelligible the mechanisms producing various ventilatory outputs in keeping with the
conditions imposed on an individual. For instance, to the
question “what sustains breathing at a level that keeps
arterial PCO2 around 40 Torr at rest?” one could answer,
following Dejours (10), that ⬃20% of the resting breathing
activity depends on a tonic drive from the carotid bodies
(CB) (41). However, not only do we have little clue about
what controls the remaining 80%, but also the physiological
meaning and relevance of this baseline CB tonic activity
remain unclear. Indeed, individuals with a low, or no ventilator response to hypercapnia, can generate the same drive
to breath resulting in eupneic breathing, just like in a
“normal” individual (38, 39). Similarly, the behavior of
PaCO2 during exercise, wherein metabolism can increase by
more than 10 times within minutes (43) dragging along
ventilation, continues to resist our sagacity, despite all the
information accumulated on the putative receptors involved
(16). In all of these conditions, the knowledge accumulated
on the CO2 or O2 sensitivity of the respiratory control
system, mediated by the central and peripheral chemoreception (25, 31), is of little help to account for the maintenance
of eupnea. This is also true in COPD or obese patients who
can display from a reduced to a virtually abolished CO2
sensitivity (14, 18) but can still appropriately regulate their
breathing, albeit at a higher PaCO2, at least when awake or
exercising (4, 17).
Plasticity (15, 28, 36), optimization (37), short-term potentiation (11, 40), after discharge (12), reconfiguration
(27), redundancy (33, 34), or degeneracy (21, 29) are some
of the properties that have been proposed to render comprehensible the operational modalities of the respiratory control
Perspectives
1554
with no circulation than at rest (23), despite similar levels of
PaCO2 or blood pressure, before CA in both conditions. It is
therefore difficult to reconcile the known effects of the main
feedback systems affecting breathing control at rest or in
exercise with the persistence of a breathing pattern proportional to V̇CO2 and the circulatory status before CA (23),
whereas the major peripheral and central inputs thought to
be responsible for this effect have vanished. Indeed, the
most relevant changes produced by a CA should have
affected respiration within one breath as soon as blood
pressure and cardiac output drop. For instance, the abrupt
disappearance of arterial (6) or central pH oscillations (30),
whether CA occurs at rest or after exercise, should depress
breathing, whereas any dramatic drop in blood pressure
should increase, with no delay, breathing via the stimulation
of the arterial baroreceptors (22) and chemoreceptors (26).
It is only after minutes that an apnea occurs, followed by the
production of gasps, likely related to a progressive anoxia of
the brain stem. The RCS behaves as if none of the initial
chemical or circulatory consequences of a cardiac arrest
were able to produce any significant effect on breathing.
Even more intriguing is the observation obtained during and
after a short period of CA in a patient with Cheynes-Stokes
(CS) breathing (1), related to chronic cardiac failure. We
found that neither the rhythmicity nor the amplitude of
ventilatory oscillations of CS breathing were affected by an
8- to 9-sc cardiac arrest, followed by a 12- to 15-s period of
low blood flow, occurring during the ascending phase of one
of the 45-s period ventilatory cycles (Fig. 1). This unaltered
CS breathing was observed despite profound changes in
cerebral blood flow and perfusion of the carotid bodies,
which should be virtually abolished during the phase of
circulatory arrest (1) and should slowly recover as a sinus
rhythm is restored. Breathing control continued to operate as
per the pre-CA metabolic and circulatory status, regardless
of the disruption of important circulatory feedback information.
These two properties imply that the respiratory control
system has a finite number of scenarios that can be used in
response to rapid and dramatic changes in metabolism or
circulation. When many, and often redundant, signals are
present (exercise), the respiratory control system seems to
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Fig. 1. A: ventricular fibrillation induced cardiac arrest after exercise in 1 sheep [reprinted from (23), with permission from Elsevier]. This example shows a long
periods of “eupneic” breathing after cardiac arrest (CA). Breath-by-breath respired CO2, respiratory flow (V̇), respiratory rate (f), minute ventilation (V̇i), and
carotid blood pressure (ABP) are displayed. Horizontal arrow represents the end of the period of exercise, which lasted 4 min (not shown). Vertical arrow is the
moment when the heart was fibrillated. Note that breathing averaged ⬃30 –35 l/min by the end of the period of exercise; ventilation increases modestly thereafter,
before stopping 2 min or so later. Breathing pattern and minute ventilation were unchanged at the onset of the cardiac arrest, and as a consequence, alveolar CO2
dropped dramatically. Note the swings in ABP during CA caused by persistent breathing activity. B: trace showing the effects of an episode of CA by pulseless
ventricular fibrillation (between the 2 arrows) and recovery occurring during the ascending phase of a periodic breathing (PB) cycle in a patient with cardiac
failure [reproduced with permission from the American College of Chest Physicians (1)]. End-tidal CO2 fraction, respiratory flow, continuous noninvasive blood
pressure (BP), and ECG are shown. Note that the discharge of the implantable defibrillators caused a transient artifact on the airflow signal. C: end-tidal CO2
and respiratory flow signals of the PB cycle during which PVF was produced are presented in black, whereas the subsequent PB cycle has been superimposed
in red line. Despite the difference in CO2 and the circulatory delay created by the period of pulseless ventricular fibrillation and recovery (circulation was altered
for more than 20 s), the production of breaths with periodic changes in tidal volume amplitude was unaffected by the cardiac arrest and recovery, except for a
transient artifact during defibrillation.
Perspectives
1555
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: P.H. conception and design of research; P.H. performed experiments; P.H. analyzed data; P.H. interpreted results of experiments; P.H. prepared figures; P.H. drafted manuscript; P.H. edited and revised
manuscript; P.H. approved final version of manuscript.
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