Respiratory Physiology & Neurobiology 181 (2012) 220–227

Contents lists available at SciVerse ScienceDirect

Respiratory Physiology & Neurobiology

journal homepage: www.elsevier.com/locate/resphysiol

Breathing during cardiac arrest following exercise: A new function of the

respiratory system?
Philippe Haouzi ∗ , Andry Van De Louw, Alice Haouzi
Division of Pulmonary and Critical Care Medicine, Pennsylvania State University, College of Medicine, Penn State Hershey Medical Center, United States

a r t i c l e i n f o a b s t r a c t

Article history: We have found in four sheep that, following a muscular exercise, minute ventilation is maintained for
Accepted 14 March 2012 34–131 s during a cardiac arrest (CA), at a magnitude (from 28.2 and 54.7 l min−1 ) similar to the level
of ventilation (and thus proportional to the metabolic rate) preceding the period of asystole. Breathing
Keywords: was maintained despite the lack of pulmonary blood flow and the cessation of the muscle contractions,
Cardiac arrest (CA) leading to a dramatic reduction in alveolar FCO2 (1.9 ± 1%). Secondly, swings in arterial blood pressure
Arterial blood pressure (ABP)
(ABP) were observed (pulse pressure of 31 ± 3 Torr) in phase with breathing movements in place of the
Asystole
cardiac activity. This “protective” response, deprived from any role in blood gas homeostasis, as circulation
Ventricular fibrillation (VF)
Respiratory control
is virtually abolished, is not predictable from the traditional respiratory control feedback systems thought
to be involved in exercise. We are presenting the view that this response, dissociated from the pulmonary
gas exchanges, is the expression of a rudimentary defense mechanism aimed at limiting the consequences
of an acute failure of the cardiac pump by the thoraco-abdominal pump.
© 2012 Elsevier B.V. All rights reserved.

1. Introduction the production of gasps (Guntheroth and Kawabori, 1975; Duffin,

One of the most fundamental and still poorly understood char-
acteristics of breathing control is certainly its ability to “track and
match” the level of metabolic activity. Such a coupling is maintained
in keeping with the inter-species and intra-species differences in
body size and metabolism (Frappell et al., 1992; Mortola, 1993,
2004), or following any increase in metabolic rate during a physical
activity (Dejours, 1963; Whipp et al., 1982, 1984; Whipp and Ward,
1990, 1991; Dempsey et al., 1997).
We have recently shown that at the onset of a cardiac arrest (CA),
fundamental physiological responses are still expressed (Haouzi
et al., 2010), limiting transiently the effects of the absence of the
cardiac contractions. The most intriguing of these responses is
certainly the persistence of the normal activity of the thoraco-
abdominal pump: in sedated sheep, the generation of normal
breath cycles is maintained at the onset of a cardiac arrest for 40 s up
to 2 min, despite the absence of flow generated by the heart (Haouzi
et al., 2010). We also found that breathing is maintained unchanged
in humans during the transient periods of an experimental fibril-
lation induced CA while testing implantable defibrillators (Haouzi
et al., 2010). This breathing activity should not be confused with
∗ Corresponding author at: Pennsylvania State University, College of Medicine,
Division of Pulmonary and Critical Care Medicine, 500 University Drive, Mail Code
H047, Hershey, PA 17033, United States. Tel.: +1 717 531 0003; fax: +1 717 531 0224.
E-mail address: phaouzi@hmc.psu.edu (P. Haouzi).
2003; Eisenberg, 2006; Bobrow et al., 2008; Haouzi et al., 2010),
with their unique and specific breathing pattern, which occur much
later along with an apnea. Incidentally, this makes breathing an
inappropriate surrogate marker of CA (Berdowski et al., 2009).
The major consequence of this observation relates to the fun-
damental physiological mechanisms, meaning, and implications of
the maintenance of a normal breathing activity with no circulation.
The challenge, which we could not resolve in our previous report,
was to reconcile the known effects of the main feedback systems
affecting breathing control during a CA with the actual breathing
pattern we observed (Haouzi et al., 2010). These feedbacks com-
prise the respiratory effects of an abrupt cessation of pulmonary
blood flow/cardiac output and arterial CO2 oscillations along with
the consequences of a drop in blood pressure and in cerebral blood
flow.
The goal of this study was to establish the relationship between
the activity of the central pattern generator of breathing, in a
“no-flow” situation, following a muscular exercise wherein the
metabolic/ventilatory levels are increased (Whipp and Ward, 1991;
Haouzi, 2006). The question is whether ventilation can be main-
tained as at rest despite the lack of blood flow and the cessation of
muscle contractions; and if it is, at what level?
The hypothesis we are testing here is that there is a genuine,
although rudimentary, adaptive response to conditions of very low
or no blood flow, which has been overlooked, as this response
cannot be predicted from the properties of traditional feedback
systems when considered separately. For all these reasons, how

1569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.resp.2012.03.011
 P. Haouzi et al. / Respiratory Physiology & Neurobiology 181 (2012) 220–227
breathing is affected at the onset of a cardiac arrest following exer-
cise remains an outstanding question.
In the present study, the ventilatory, gas exchange and arterial
blood pressure (ABP) responses were determined breath-by-breath
during VF induced CA following electrically induced muscle con-
tractions of the hindlimbs in sedated spontaneously breathing
sheep (Haouzi and Chenuel, 2005; Haouzi et al., 2010).
2. Methods
We have previously reported the ventilatory responses follow-
ing a cardiac arrest in resting conditions (Haouzi et al., 2010). In this
previous study, every episode of ventricular fibrillation was termi-
nated by delivering a 20 J biphasic DC shock upon the third gasp
following respiratory arrest. This allowed us to produce several
episodes of cardiac arrest at rest in the same animal, in the course
of a 4–5 h study, as we found that breathing returned to baseline
within less than 20 min, with rapidly reversible change in arterial
pH. The following protocol was applied in 4 of these animals.
2.1. Animal preparation
Four sheep (43–55 kg) were pre-medicated with ketamine
(40 mg kg−1 , IM), with subsequent anesthesia induced with a load-
ing dose of sodium pentobarbital (6 mg kg−1 , iv). Procedures were
approved by the local Institutional Animal Care and Use Commit-
tee. Sedation was maintained throughout the experiment using
urethane (25%, 30 mg kg−1 , IV) and ␣-chloralose (5%, 150 mg kg−1 ,
IV) solution. Animals were tracheotomized, and a catheter was
introduced into the left carotid artery to monitor arterial blood
pressure. Another catheter was placed in the right external jugu-
lar vein for injections of anesthetic agents. At the termination of
the experiment, sheep were euthanized with sodium pentobarbi-
tal (200 mg kg−1 ) and potassium chloride (∼9 meq kg−1 ) injected
IV.
2.2. Measurements
Animals breathed through a two-way valve (1420 Series, Hans
Rudolph, KS, USA), coupled to the tracheal cannula via a cali-
brated pneumotachograph (Fleisch No. 2, Phipps and Bird, VA, USA).
Expired CO2 was analyzed using a fast responding infrared analyzer
(model #17630, Vacumed, Ventura CA, USA). Oxygen uptake was
determined from the measurement of mixed expired O2 fraction
collected in an expiratory bag (model #17630, Vacumed, Ventura
CA, USA) along with the corresponding level of expired minute
ventilation. Arterial carotid BP was continuously recorded using a
pressure transducer (Model MLT0380/D, AD Instruments, CO, USA).
The transducer was calibrated before each experiment using a mer-
cury column. All signals were collected with an analog–digital data
acquisition system (Powerlab 16/30, ML880, AD Instruments, CO,
USA) at a rate of 200 Hz.
2.3. Fibrillation protocol
A 7 French ICD lead (Boston Scientific, Endotak Reliance G 0185)
was advanced into the right ventricle. The tip of the lead was then
screwed into the myocardium. A Medtronic Intrinsic DR ICD gen-
erator (Medtronic, Inc., Minneapolis, Minnesota) was implanted
subcutaneously. VF was induced using high-frequency burst pacing
(50 Hz, 8 V). Induction of ventricular fibrillation was confirmed by
the surface ECG.
221
2.4. Muscle contractions prior to CA
The hindlimbs were shaved, and two pairs of large electrodes
with conductive gel were placed on both thighs. Muscle contrac-
tions were generated using a modulated stimulation frequency
of 40 Hz, applied for 2 s every 4 s. Current intensity was set to
between 10 and 15 mA with a rise and fall time of 0.5 s. Muscle
contractions during this stimulation protocol produced a rhyth-
mic extension and adduction of the hindlimbs resembling dynamic
exercise. The contractions were performed against a resistance con-
sisting of rubber bands attached to the distal part of the limbs and
were of sufficient intensity to at least double minute ventilation
and metabolism (Haouzi and Chenuel, 2005).
2.5. Protocol
After a period of at least 15 min of quiet and stable breathing, at
least 30 min after a previous FV, contractions were produced and
maintained for 5 min prior to experimental CA and terminated upon
initiation of VF.
Ventricular fibrillation was terminated by delivering a 20 J
biphasic DC shock upon the first gasps following respiratory
arrest.
2.6. Data analysis
Data were analyzed offline using Chart software (ADInstru-
ments). The flow signal was integrated for breath-by-breath
measurement of tidal volume (VT ), and derived for the deter-
mination of gas acceleration. Breathing frequency and minute
ventilation (in BTPS conditions) were determined breath-by-
breath. All data are expressed as individual results (in the figures)
and as mean ± SD or the median.
Each cardiac arrest was analyzed as a separate event. The arterial
blood pressure and ventilatory parameters were analyzed during
the last minute of exercise preceding the CA and during the entire
period of cardiac arrest when eupneic breathing was maintained.
Data were compared using Wilcoxon signed-ranked tests, p < 0.05
was regarded as significant.
In our previous report (Haouzi et al., 2010), we were surprised
to see that ABP did not appear to follow the change in lung vol-
ume (and thus the expected change in trans-pulmonary pressure).
We therefore analyzed the change in ABP more systematically in
keeping with the respiratory cycle (inspiration and expiration) as
follows: the total pressure produced by the respiratory system
at a time t (Prs(t)) to mobilize a volume V at a flow V , and an
acceleration V can be regarded as the sum of the elastic pressure
(proportional to the elastance (E) and the volume of gas mobi-
lized (V)), the resistive pressure (proportional to the resistance
(R) and the flow of gas mobilized (V )) and inertial pressure (pro-
portional to the inertia (I) and the acceleration of gas mobilized):
Prs(t) = E · V(t) + R · V (t) + I · V (t). The multivariate linear equation
was therefore computed between ABP, V, V and V to determine
the relative weight of each of the 3 respiratory variables in the
generation of ABP. Four parameters were therefore obtained, three
proportional to V, V and V respectively and one corresponding to
mean ABP. Computations were performed on 3 consecutive breaths
at the peak of the oscillations in ABP during a given episode of
CA.
3. Results
3.1. Effects of muscle contractions
An example of the response to electrically induced mus-
cle contractions is shown in Fig. 1. Responses were identical
222 P. Haouzi et al. / Respiratory Physiology & Neurobiology 181 (2012) 220–227
Fig. 1. Panel A: Example of the ventilatory effects of exercise and ventricular fibril-
lation induced cardiac arrest in one sheep. Breath-by-breath expired CO2 (PETCO2 ),
instantaneous respiratory flow (V ), Carotid blood pressure (ABP), respiratory rate
(f), tidal volume (VT ) and minute ventilation (V̇E ) are displayed. The horizontal arrow
represents the period of exercise. The vertical arrow is the moment when the heart
was stopped. Note that breathing increases during the period of exercise by almost 4
times while ABP decreases due to peripheral vasodilation. Clearly, ventilation does
not stop when the heart stops. Panel B: magnification of the transition between
exercise and cardiac arrest shown in panel A. Same legends as in panel A. Note that
breathing is unchanged at the onset of the cardiac arrest, remaining at the same
level as during exercise, then minute ventilation continues to rise reaching values
of above 40 l min−1 . Consequently, alveolar CO2 decreases dramatically.
to those we have already reported (Haouzi and Chenuel, 2005;
Haouzi et al., 2010) consisting in an increase in breathing asso-
ciated to a peripheral vasodilation. Indeed, ventilation increased
in an exponential fashion from 9.71 ± 4.32 l min−1 at rest to
34.32 ± 6.87 l min−1 during exercise (p < 0.01) while pulmonary O2
uptake increased from 401 ± 249 to 1081 ± 249 ml min−1 (p < 0.01).
Mean ABP decreased significantly (as illustrated in Fig. 1) from
112 ± 10 to 83 ± 9 mmHg (p < 0.01). The reduction in ABP mainly
affected the diastolic pressure, which decreased from 104 ± 6 to
69 ± 5 mmHg (p < 0.01), while the systolic pressure did not change
significantly (144 ± 15 mmHg at rest vs. 136 ± 5 mmHg during mus-
cle contractions). Endtidal PCO2 did not change significantly from
resting baseline values throughout the period of muscle con-
tractions (39.0 ± 4 vs. 37.2 ± 4 Torr during exercise and at rest
respectively).
3.2. Cardiac arrest
Five episodes of ventricular fibrillation (VF) were triggered
in the 4 sheep (one sheep had 2 episodes of VF separated by
60 min). VF produced an immediate and complete disappear-
ance of cardiac activity on the ABP signal. Mean ABP decreased
within seconds from 83 ± 9 mmHg to 23 ± 3 mmHg (Figs. 1 and 2).
Despite the cessation of cardiac activity, ventilation remained
unchanged for 15 s (36.72 ± 9.46 l min−1 ), before beginning to
increase toward a maximum of 46.16 ± 24.89 l min−1 , followed by
respiratory arrest (apnea). The median of total duration of eup-
neic breathing before respiratory arrest was 67 s (ranging from 33
to 131 s), and minute ventilation averaged 39.85 ± 12.19 l min−1
(range 28.21–54.77 l min−1 , median 44.61 l min−1 ) across this
entire period (NS vs. exercise). The relatively high rate of pul-
monary ventilation with a virtual absence of pulmonary blood flow
caused FETCO2 to decrease dramatically, averaging only 1.9 ± 1.0%
(range 0.8–3.2%, median 2.6%, p < 0.001 vs. exercise) when breath-
ing stopped (Figs. 1–3). The apneic period was interrupted by
typical gasps occurring later into the apnea (Fig. 2).
Throughout all the period of eupneic breathing, ABP dis-
played obvious oscillations in phase with the breathing cycles
(Figs. 1, 2 and 4): peak, nadir and mean values of these blood pres-
sure oscillations averaged 36 ± 3, 9 ± 4 and 28 ± 7 Torr respectively.
The frequency of the swings in ABP was identical to the breath-
ing frequency (36 ± 3 cycles min−1 ). Following the cessation of the
respiratory activity, mean ABP stabilized at a level of 15 ± 3 mmHg
(reflecting mean filling pressure) without further oscillations.
Clearly the changes in ABP, which occurred in phase with the
persistent breathing cycles, did not follow the variations in lung
volume (Figs. 4 and 5). Rather ABP appeared to follow factors tem-
porally related to gas flow and to a lesser extent to the deceleration
of gas in the airways. This was observed for all breathes without
a single exception. As illustrated in Fig. 5, ABP started to increase
when inspiratory flow decreased, but before expiration. A multi-
variate regression analysis between ABP, volume, flow and accel-
eration of the gas confirmed these observations (Fig. 5): ABP was
accurately described as a function of V, V and V (R2 = 0.83 ± 0.1)
with corresponding parameters averaging 0.03 ± 0.25 mmHg l−1 ,
−5.21 ± 1.41 mmHg l−1 s−1 and −7.64 ± 6.33 mmHg l−1 s−2 respec-
tively (Fig. 5). In other words, factors associated with gas flow and
acceleration rather than volume appear to be essential in the pro-
duction of ABP fluctuations during CA.
4. Discussion
We found that not only does an effective activity of the cen-
tral pattern generator for breathing persist during 33–131 s at the
onset of a VF induced cardiac arrest following muscle contractions,
but ventilation remains at or above the level that was generated
prior to CA. Since breathing increases in direct proportion to the
level of metabolic activity during and following exercise (Dejours,
1959; Whipp and Ward, 1991; Haouzi, 2006), ventilation was much
higher during CA following exercise than at rest, before an apnea
occurred (Fig. 6). The resulting high ventilation/perfusion ratio led
to an even more severe reduction in alveolar PCO2 (and rise in PAO2 )
than we previously found during a CA at rest (Fig. 6). Finally, as
a result of the elevated respiratory activity, swings in ABP were
produced at a similar level than at rest despite exercise induced
vasodilation (ABP was much lower during muscle contractions than
at rest). The meaning and implications of these findings are dis-
cussed in the following paragraphs.
4.1. Breathing with “no heart beat”
What drives breathing during CA following exercise? The ques-
tion is even more complex than at rest as one should clarify not only
why is breathing maintained but why and how it is maintained at
a much higher level than at rest. Breathing control and metabolic
rate are closely linked, maintaining blood gas homeostasis when
metabolism varies (Whipp and Ward, 1991): during a dynamic
muscular exercise, alveolar ventilation increases in proportion to
the metabolic rate preventing PACO2 to increase and PAO2 to drop.
The physiological ventilatory changes associated with the variation
 P. Haouzi et al. / Respiratory Physiology & Neurobiology 181 (2012) 220–227 223

Fig. 2. Other example of ventricular fibrillation induced cardiac arrest following exercise. This example shows one of the longest periods of eupneic breathing following CA.
Same legend as in Fig. 1. Note the swings in ABP during breathing at the onset of CA and the drop in alveolar FCO2 . When breathing stops after about 2 min, the apneic period
is interrupted by typical gasps.

in pulmonary gas exchange are fast: the fastest components of the
ventilatory response at the onset of a step change in work load
occurs within one breath (Dejours et al., 1957; Dejours, 1959, 1963,
1989; Dempsey et al., 1997), then ventilation continues to rise fol-
lowing factors temporally associated with the change in pulmonary
gas exchange (Whipp et al., 1982). Similarly minute ventilation
decreases within one breath following the cessation of exercise,
then declines exponentially with a 1 min time constant toward rest-
ing level (Dejours, 1959). The typical decline in minute ventilation
during the off-transient and the recovery of muscular exercise was
abolished during CA. Despite the dramatic reduction in pulmonary
gas exchange and the cessation of the muscle contractions, venti-
lation remained constant, increasing at an even higher level after
10–15 s. The challenge is therefore to clarify how all the putative
“respiratory feedbacks” operating during exercise recovery, could
interact with those produced by a cardiac arrest resulting in the
persistence of breathing at the onset of CA.
Briefly, mechanisms which should decrease breathing when
muscle contractions cease include the sudden interruption of all
mechanical feedback related to limb movements and muscle con-
tractions traveling through small and myelinated fibers (Mense and
Stahnke, 1983). Similarly all mechanisms potentially sensing the

Fig. 3. Left panel: Individual values (range, mean ± SD) of the duration of the periods of breathing in each CA. Middle panel: individual values (range mean ± SD) 1 min before
and during the period of CA wherein breathing is maintained following exercise. There was no significant difference between the level of ventilation before and after CA.
Right panel: individual values of alveolar FCO2 1 min before and during the period of CA (range, mean ± SD). Endtidal CO2 decreased dramatically during CA following exercise
(*significant difference between pre and post CA).
224 P. Haouzi et al. / Respiratory Physiology & Neurobiology 181 (2012) 220–227

Fig. 4. Example of recording obtained in one sheep showing respiratory flow and carotid blood pressure changes before exercise (A), just prior (B) to and during (C) the first
minute of CA following exercise. Note that ABP is produced during CA through the persistence of an active expiratory activity. Panel D shows the individual values of ABP
prior to and during CA.

rate of venous return, blood flow to the limbs, pulmonary blood
flow (see Haouzi, 2006 for review), or stimuli related to the oscilla-
tions in arterial PCO2 at the chemoreceptor level (Band et al., 1973,
1980), should rapidly decrement the drive to breath as soon as
exercise stops. During a CA, these mechanisms postulated to play a
role in exercise hyperpnea are not effective anymore to reduce the
drive to breath in keeping to the level of metabolic/gas exchange
level, or some of its cardio-vascular components (Kostreva et al.,
1979; Lloyd, 1984; Huszczuk et al., 1986). The fact that ventilation
persisted at the same level despite an absence of CO2 pulmonary
blood flow induced by exercise also contradicts series of experi-
mental data suggesting an obligatory matching or coupling between
CO2 pulmonary blood flow and respiratory control during exer-
tion (Phillipson et al., 1981). On the other hand, the anticipated

Fig. 5. Left panel: Example of a recording in one sheep showing the acceleration, flow and volume of the respiratory gas along with ABP during CA. ABP has also been
represented with a reverse axis to illustrate the similarity between the flow and ABP profiles. Note that 1 – ABP follows clearly respiratory flow and 2 – the level of “systolic”
pressure is dictated by the level of expiratory flow. Right panel displays a graphic illustration of the relative weight of the parameters of the multiple linear regression analysis
used between V , V , V and ABP. In this example (one breath is shown), like in all episodes of CA, factors related to respiratory flow dictate the major part of the changes in
ABP. Acceleration affected the signal during the transition phase between expiration and inspiration only. Lung volume had virtually no influence on ABP.
 P. Haouzi et al. / Respiratory Physiology & Neurobiology 181 (2012) 220–227 225

Fig. 6. Panel A displays the relationship between the level of ventilation prior and during CA. Closed circle are the data reported in the present study, while the open circles
represent 8 episodes of CA in the same animals performed at rest, at least 30 min before and 30 min after the episode of CA during exercise. These data have already been
reported elsewhere (Haouzi et al., 2010). Clearly, the higher the level of breathing prior to CA, the larger the level of breathing during the period of eupneic breathing. Panels
B and C display the relationship between endtidal FCO2 and the duration of eupneic breathing (panel B) or the total volume of gas mobilized during this period (panel C). The
reduction of CO2 in the alveolar gas depends on the duration of the period of relative hyperventilation (total volume of gas mobilized) during CA. See Section 4 for further
details.

consequences of a cardiac arrest on blood pressure should have
stimulated breathing with no delay: this response, which should
occur within one breath (Brunner and Kligman, 1993), involves the
arterial baroreflex and chemoreflex, being elicited by the severe and
immediate reduction in ABP (Brunner and Kligman, 1993; Saupe
et al., 1995; Haouzi et al., 2003). Just like at rest, ABP did drop imme-
diately but with no increase in breathing for several breaths. We
previously suggested that none of the circulatory feedback mech-
anism(s) stimulating breathing during a CA can be reconciled with
the temporal profile and the amplitude of the breathing pattern
during a CA.
Breathing control continues to operate as per the pre-CA
metabolic demand, despite a profound disruption of the feedback
systems postulated to be involved in the control of exercise hyperp-
nea (see Whipp et al., 1984; Eldridge and Waldrop, 1991 for debate
and discussion) as well as those produced by the cessation of circu-
lation. As illustrated in Fig. 6, breathing level appears to be dictated
by the drive to breath prior to the cardiac arrest.
Could some of the mechanisms stimulating breathing in propor-
tion to the change in metabolism in exercise be still active during
a CA, regardless of the absence of circulation and muscle activ-
ity? The arterial blood gas composition at this moderate level of
exercise was not different from rest, making unlikely that the chem-
ical control of breathing could account for the difference between
rest and exercise (the blood exposed to the peripheral or cen-
tral chemoreceptors is in a no flow condition the same whether
at rest or following muscle contractions). However, other blood
born factors may persist in proportion to the metabolic activity,
for instance, the higher concentration of K+ in the blood bathing
the carotid bodies during exercise (see Whipp and Ward, 1991 for
review), which drops rapidly during the recovery from exercise
due to muscle reuptake, may well be still present during a CA
(Paterson, 1992). Muscle afferent fibers responding to ischemia,
rather than to muscle tension, have been proposed to be involved
in the integrated cardio-respiratory response to exercise (Kaufman,
1995). Group III and IV afferent fibers are indeed stimulated during
ischemic contractions (Mense and Stahnke, 1983; Kaufman et al.,
1984). However, the role of this sensing mechanism on the con-
trol of exercise hyperpnea and its recovery is far from clear. We
and others have shown that when the circulation to and from the
limbs is impeded during recovery from exercise, i.e. following con-
tractions, breathing is inhibited and not stimulated (Dejours et al.,
1957; Rowell et al., 1976; see also Haouzi et al., 2004 for review),
unless ischemia is maintained for more than a minute.
Another putative mechanism that could still be operative dur-
ing a CA is the progressive distension of the venous side of the
circulation which occurs during CA, as blood shifts from the arte-
rial compartment to the highly compliant venous system as soon as
the heart stops (Guyton et al., 1954). We postulated that this could
constitute a stimulus to breathe during exercise through the pres-
surization of the post-capillary/venous compartment of the muscle
capillary bed, involving in turn unmyelinated fibers in the skeletal
muscle (Haouzi et al., 2004).
Since the normal decline of breathing observed following exer-
cise is abolished during a CA, the possibility that the maintenance
of spontaneous breathing represents an active strategy of the cen-
tral pattern generator for breathing should be explored. The abrupt
cessation of the cardiac activity is a unique condition wherein, at
the very same time, ABP drops and pulmonary and systemic blood
flow cease, while venous pressure increases. The effects of the com-
bination of these signals have never been investigated, but they
could represent a specific source of information for the medullary
226 P. Haouzi et al. / Respiratory Physiology & Neurobiology 181 (2012) 220–227
respiratory neurons to keep the same drive to breath, as a “safety
mechanism”, until brainstem anoxia occurs. Such a response is
different in nature from any phenomenon of short term mem-
ory or after discharge which may well operate following exercise
(Eldridge, 1977), but which cannot prevent a decline of the respi-
ratory output toward resting levels. The present observation could
well reflect the attempt of the respiratory pump to compensate for
the lack of cardiac pumping during CA.
We have however no explanation to offer to account for the
rather variable duration of eupneic breathing. It is clear that the
animal that had the longest period of breathing during CA at rest
was also the one that displayed the longest period of breathing
following exercise, but this duration was so variable, in keeping
with the number of tests, that no correlation could be established.
Clearly, medullary hypoxia should develop during a CA after a delay,
leading to anoxia induced apnea, followed by the production of
gasps; but we could not find any simple predicting factor explaining
this variability: neither the level of breathing prior to CA nor the
level of ABP during CA were different among the various tests.
4.2. Maintenance of breathing as a survival strategy
The present observation also impacts the pathophysiology and
treatment of CA since the vast majority of sudden cardiac deaths
in young individuals, comprising children, athletes and soldiers,
occurs during a muscular exercise (Drehner et al., 1999; Amital
et al., 2004; Balady, 2004; Eckart et al., 2004; Borjesson and
Pelliccia, 2009; Maron, 2010). If some form of strategy of survival
can be generated by the persistence of an automatic activity of the
thoraco-abdominal pump in keeping with the level of breathing
prior to CA (Fig. 6), our current views of cardiac asystole should be
modified accordingly (see following section).
4.2.1. Generation of blood pressure changes
The effects of the ventilatory activity on ABP were obvious.
Naturally occurring respiration during a CA is however different
from chest compressions, in the sense that infra-atmospheric pres-
sures are generated in the thorax during spontaneous inspiration,
increasing in turn thoracic blood volume (Cave et al., 2011). We
found that the fluctuations in ABP generated by the spontaneous
breathing activity at the onset of a CA were not the direct result
of the change in intrapleural pressure, a function of volume, but
were dictated by factors proportional to flow and even accelera-
tion (Fig. 3). The mechanisms of ABP production during a cardiac
arrest are rather complex (Kern, 2009): we found that during inspi-
ration, ABP dropped below the mean filling pressure (Guyton et al.,
1954), this was even more true during augmented breaths or sighs
(Figs. 2 and 4). The magnitude and briskness of the reduction in
ABP during the diastolic phase (inspiration) suggest that the aortic
valves may not be continent during CA in our sheep model.
The clinical relevance of respiratory driven ABP oscillations
relies on their ability to produce blood flow (Mitchell and Nichol,
2009). The latter will depend on the pressure gradients created
between the venous and arterial sides of the circulation through-
out the breathing cycle. We have suggested that the effects of
increasing rhythmically intra-thoracic pressure should not result
in a “static blood column moving to and fro”, as the arterial and the
venous sides of the circulation are to be pressurized and depressur-
ized with a positive “arterial-venous” pressure gradient. In other
words, when the thoraco-abdominal pump “ejects” blood toward
the peripheral vascular bed, pressures do not equilibrate in the
venous systems at the same rate as in the arterial compartment
(Kern, 2009). Due to the large compliance of the former, pressure
should increase much faster and higher in the latter, creating in turn
spontaneous blood flow in the body. After all, the possibility to gen-
erate systemic blood flow constitutes the rationale for using chest
compressions during cardio-pulmonary resuscitation (Kern, 2009;
Mitchell and Nichol, 2009). Indeed, cough CPR, chest compression
with or without lung inflation, CPR with active compression and
decompression, abdominal compression with lung inflation, or the
inflation of a vest have long been proposed to be able to replace the
cardiac pump (Berg et al., 2011; Cave et al., 2011). In addition, large
breaths such as those produced during gasping (Eisenberg, 2006;
Bobrow et al., 2008; Suzuki et al., 2009) or during cough (Criley
et al., 1976) can generate cerebral blood flow (Suzuki et al., 2009)
allowing patients to remain conscious during a CA (Criley et al.,
1976).
This neo-circulatory system cannot allow circulation to be self-
sustained by means of respiratory movements even after exercise.
Incidentally, any spontaneous respiratory effort against a partially
closed glottis should have been able to generate much higher intra-
thoracic pressure, a phenomenon that could not be observed in
tracheostomized animals, but which can be involved during a CA
in humans (see also next paragraph).
4.2.2. Modification of the alveolar gas during CA
The second consequence of the maintenance of breathing during
CA after exercise is a very high (almost infinite) pulmonary ven-
tilation/perfusion ratio resulting in a profound “hypocapnic” and
“hyperoxic” alveolar gas. This effect is obviously related to the dura-
tion of the period of eupneic breathing, its amplitude (Fig. 6), and
the volume and composition of the blood in the pulmonary cir-
culation. The much higher level of breathing during CA following
exercise counteracted the higher volume of blood and CO2 present
in the lung. This can be seen in Fig. 6C, where a similar level of
alveolar CO2 is reached at rest and following exercise, despite the
higher level of ventilation in the latter.
Whenever CPR is initiated following a muscular exercise,
one can predict that blood flow redistribution toward the post-
exercising muscles will make it essentially impossible to generate
the level of cardiac output needed to maintain adequate coronary
and cerebral perfusion pressure (Tiangco and Haouzi, 2010). More
importantly the pulmonary circulation will be “contaminated” by a
venous blood coming preferentially from the post exercising mus-
cles, which have the lowest vascular impedance, a high metabolic
activity and O2 deficit. This will occur even though blood flow
generated during CPR is low. Consequently, although a proper the-
oretical and experimental frame of reference is lacking to fully
understand the effects of an exercise on CA, one could anticipate
that following exercise, the level of ventilation compatible with
a resuscitation should be several fold higher than the levels rec-
ommended by the current guidelines (ECC Committee, 2005). The
present results may prove these predictions incorrect. The actual
composition of the gas present in the FRC (low PACO2 and high
PAO2 ) whenever circulation resumes during CPR or spontaneously
should delay the drop in blood oxygenation and rise in PaCO2 /pH
of the blood which would have occurred if ventilation and cardiac
activity were to cease at the same time.
Just like for the circulatory changes, the effects of CA on breath-
ing remain to be described in “physiological conditions”, i.e. in a
non-intubated or non-tracheostomized model, since partial closure
of the glottis during inspiratory movements may create conditions
of upper airways obstruction, which can minimize this effect on the
alveolar gas composition we have observed in our sheep model. As
pointed out in the previous paragraph, this in turn should greatly
magnify the circulatory effects of breathing, making the thoracic
pump a much more efficient circulatory pump than with active
open upper-airways. It should be pointed out, however, that 1 –
gasping which occurs later into CA does produce respiratory flow
and 2 – at the onset of a CA in humans, respiratory flow pattern
is unchanged (Haouzi et al., 2010), suggesting that upper-airway
muscles are active during inspiration in CA.
 P. Haouzi et al. / Respiratory Physiology & Neurobiology 181 (2012) 220–227
5. Conclusions
Breathing is maintained for about 70 s after the onset of a CA fol-
lowing exercise. The level of ventilation is dictated by the drive to
breathe prior to CA. The mechanisms controlling ventilation during
this period remain unclear. Nevertheless, the resulting reduction in
CO2 store in the lungs was dramatic and the corresponding increase
in FAO2 would certainly oppose during CPR some of the conse-
quences of a high metabolic activity. Finally, ABP oscillations, albeit
modest, occurred in phase with breathing.
We postulate that the persistence of a drive to breathe at the
onset of CA may represent a genuine rudimentary form of control of
circulation and gas exchange and an adaptation to a ‘no-blood flow’
situation. The characteristics of respiratory control at the onset of
a CA should be viewed as a protective mechanism that might be
involved in all sorts of self-terminating arrhythmia-induced CA or
syncopal episodes.
Acknowledgments
The authors are grateful to Dr. Harold Bell for his help with the
sheep experiments and for Dr. Mario Gonzales for his inputs and
technical support in developing the model of ventricular fibrilla-
tion.
This project was partly supported by Pennsylvania State Depart-
ment of Health, RFA number 08-07006.
References
Amital, H., Glikson, M., Burstein, M., Afek, A., Sinnreich, R., Weiss, Y., Israeli, V.,
2004. Clinical characteristics of unexpected death among young enlisted mil-
itary personnel: results of a three-decade retrospective surveillance. Chest 126,
528–533.
Balady, G.J., 2004. Sudden cardiac death in young military recruits: guarding the
heart of a soldier. Ann. Intern. Med. 141, 882–884.
Band, D.M., Ebden, P., Semple, S.J.G., Wolff, C.B., 1973. Effect on respiration of changes
in the form of the naturally occurring oscillation in arterial pH. Acta Neurobiol.
Exp. 33, 113–122.
Band, D.M., Wolff, C.B., Ward, J., Cochrane, G.M., Prior, J.G., 1980. Respiratory oscil-
lations in arterial carbon dioxide tension as a control signal in exercise. Nature
283, 84–85.
Berdowski, J., Beekhuis, F., Zwinderman, A.H., Tijssen, J.G., Koster, R.W., 2009. Impor-
tance of the first link: description and recognition of an out-of-hospital cardiac
arrest in an emergency call. Circulation 119, 2096–2102.
Berg, R.A., Hemphill, R., Abella, B.S., Aufderheide, T.P., Cave, D.M., Hazinski, M.F.,
Lerner, E.B., Rea, T.D., Sayre, M.R., Swor, R.A., 2011. Part 5: adult basic life support:
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care. Circulation 122, S685–S705.
Bobrow, B.J., Zuercher, M., Ewy, G.A., Clark, L., Chikani, V., Donahue, D., Sanders, A.B.,
Hilwig, R.W., Berg, R.A., Kern, K.B., 2008. Gasping during cardiac arrest in humans
is frequent and associated with improved survival. Circulation 118, 2550–2554.
Borjesson, M., Pelliccia, A., 2009. Incidence and aetiology of sudden cardiac death in
young athletes: an international perspective. Br. J. Sports Med. 43, 644–648.
Brunner, M.J., Kligman, M.D., 1993. Hemodynamic and respiratory responses to
carotid sinus pressure alteration in experimental hypertension. J. Appl. Physiol.
74, 1274–1279.
Cave, D.M., Gazmuri, R.J., Otto, C.W., Nadkarni, V.M., Cheng, A., Brooks, S.C., Daya,
M., Sutton, R.M., Branson, R., Hazinski, M.F., 2011. Part 7: CPR techniques and
devices: 2010 American Heart Association Guidelines for Cardiopulmonary
Resuscitation and Emergency Cardiovascular Care. Circulation 122, S720–S728.
Criley, J.M., Blaufuss, A.H., Kissel, G.L., 1976. Cough-induced cardiac compres-
sion. Self-administered from of cardiopulmonary resuscitation. JAMA 236,
1246–1250.
Dejours, P., 1959. Regulation of ventilation during muscular exercise in man. J. Phys-
iol. (Paris) 51, 163–261.
Dejours, P., 1963. The regulation of breathing during muscular exercise in man: a
neuro-humoral theory. In: Cunningham, D.J.C., Lloyd, B.B. (Eds.), The Regulation
of Human Respiration. Blackwell Scientific, Oxford, pp. 535–547.
Dejours, P., 1989. From comparative physiology of respiration to several problems
of environmental adaptations and to evolution. J. Physiol. 410, 1–19.
Dejours, P., Mithoefer, J.C., Raynaud, J., 1957. Evidence against the existence of spe-
cific ventilatory chemoreceptors in the legs. J. Appl. Physiol. 10, 367–371.
Dempsey, J.A., Forster, H.V., Ainsworth, D.M., 1997. Regulation of hyperpnea, hyper-
ventilation and respiratory muscle recruitment during exercise. In: Dempsey,
J.A., Pack, A.I. (Eds.), Regulation of Breathing, vol. 79. Marcel Dekker Inc., New
York, pp. 1065–1134.
Drehner, D., Neuhauser, K.M., Neuhauser, T.S., Blackwood, G.V., 1999. Death among
U.S. Air Force basic trainees, 1956 to 1996. Mil. Med. 164, 841–847.
227
Duffin, J., 2003. A commentary on eupnoea and gasping. Respir. Physiol. Neurobiol.
139, 105–111.
ECC Committee, S.a.T.F.o.t.A.H.A., 2005. 2005 American Heart Association guidelines
for cardiopulmonary resuscitation and emergency cardiovascular care. Circula-
tion 112, 1–203.
Eckart, R.E., Scoville, S.L., Campbell, C.L., Shry, E.A., Stajduhar, K.C., Potter, R.N., Pearse,
L.A., Virmani, R., 2004. Sudden death in young adults: a 25-year review of autop-
sies in military recruits. Ann. Intern. Med. 141, 829–834.
Eisenberg, M.S., 2006. Incidence and significance of gasping or agonal respirations
in cardiac arrest patients. Curr. Opin. Crit. Care 12, 204–206.
Eldridge, F.L., 1977. Maintenance of respiration by central neural feedback mecha-
nisms. Fed. Proc. 36, 2400–2404.
Eldridge, F.L., Waldrop, T.G., 1991. Neural control of breathing during exercise. In:
Whipp, B.J., Wasserman, K. (Eds.), Exercise: Pulmonary Physiology and Patho-
physiology. Marcel Dekker, New York, pp. 309–370.
Frappell, P., Lanthier, C., Baudinette, R.V., Mortola, J.P., 1992. Metabolism and ven-
tilation in acute hypoxia: a comparative analysis in small mammalian species.
Am. J. Physiol. 262, R1040–R1046.
Guntheroth, W.G., Kawabori, I., 1975. Hypoxic apnea and gasping. J. Clin. Invest. 56,
1371–1377.
Guyton, A.C., Polizo, D., Armstrong, G., 1954. Mean circulatory filling pressure
measured immediately after cessation of heart pumping. Am. J. Physiol. 179,
261–267.
Haouzi, P., 2006. Theories on the nature of the coupling between ventilation and gas
exchange during exercise. Respir. Physiol. Neurobiol. 151, 267–279.
Haouzi, P., Chenuel, B., 2005. Control of arterial PCO2 by somatic afferents in sheep.
J. Physiol. 569, 975–987.
Haouzi, P., Chenuel, B., Chalon, B., Braun, M., Bedez, Y., Tousseul, B., Claudon, M., Gille,
J.P., 2003. Isolation of the arterial supply to the carotid and central chemorecep-
tors in the sheep. Exp. Physiol. 88, 581–594.
Haouzi, P., Chenuel, B., Huszczuk, A., 2004. Sensing vascular distension in skele-
tal muscle by slow conducting afferent fibers: neurophysiological basis and
implication for respiratory control. J. Appl. Physiol. 96, 407–418.
Haouzi, P., Ahmadpour, N., Bell, H.J., Artman, S., Banchs, J., Samil, S., Gonzalez, M.,
Gleeson, K., 2010. Breathing pattern during cardiac arrest. J. Appl. Physiol. 109,
405–411.
Huszczuk, A., Whipp, B.J., Oren, A., Shors, E.C., Pokorski, M., Nery, L.E., Wasserman,
K., 1986. Ventilatory responses to partial cardiopulmonary bypass at rest and
exercise in dogs. J. Appl. Physiol. 61, 575–583.
Kaufman, M.P., 1995. Afferents from limb skeletal muscle. In: Dempsey, J.A., Pack,
A.I. (Eds.), Regulation of Breathing, vol. 79. Dekker, New York, pp. 583–616.
Kaufman, M.P., Rybicki, K.J., Waldrop, T.G., Ordway, G.A., 1984. Effect of ischemia
on responses of group III and IV afferents to contraction. J. Appl. Physiol. 57,
644–650.
Kern, K., 2009. Pathophysiology of Cardiac Arrest. Lippincott Willians and Wilkins,
Philadelphia.
Kostreva, D.R., Hopp, F.A., Zuperku, E.J., Kampine, J.P., 1979. Apnea, tachypnea, and
hypotension elicited by cardiac vagal afferents. J. Appl. Physiol. 47, 312–318.
Lloyd Jr., T.C., 1984. Effect on breathing of acute pressure rise in pulmonary artery
and right ventricle. J. Appl. Physiol. 57, 110–116.
Maron, B.J., 2010. National electrocardiography screening for competitive athletes:
feasible in the United States? Ann. Intern. Med. 152, 324–326.
Mense, S., Stahnke, M., 1983. Responses in muscle afferent fibres of slow conduction
velocity to contractions and ischaemia in the cat. J. Physiol. (Lond.) 342, 383–397.
Mitchell, S., Nichol, G., 2009. Sudden Cardiac Death: Epidemiology, Pathophysiology
and Future Direction. Lippincott Willians and Wilkins, Philadelphia.
Mortola, J.P., 1993. Hypoxic hypometabolism in mammals. News Physiol. Sci. 8,
79–82.
Mortola, J.P., 2004. Implications of hypoxic hypometabolism during mammalian
ontogenesis. Respir. Physiol. Neurobiol. 141, 345–356.
Paterson, D., 1992. Potassium and ventilation during exercise. J. Appl. Physiol. 72,
811–820.
Phillipson, E.A., Duffin, J., Cooper, J.D., 1981. Critical dependence of respiratory rhyth-
micity on metabolic CO2 load. J. Appl. Physiol. 50, 45–54.
Rowell, L.B., Hermansen, L., Blackmon, J.R., 1976. Human cardiovascular and respi-
ratory responses to graded muscle ischemia. J. Appl. Physiol. 41, 693–701.
Saupe, K.W., Smith, C.A., Henderson, K.S., Dempsey, J.A., 1995. Respiratory and car-
diovascular responses to increased and decreased carotid sinus pressure in
sleeping dogs. J. Appl. Physiol. 78, 1688–1698.
Suzuki, M., Funabiki, T., Hori, S., Aikawa, N., 2009. Spontaneous gasping increases
cerebral blood flow during untreated fatal hemorrhagic shock. Resuscitation 80,
109–112.
Tiangco, D., Haouzi, P., 2010. Breathing requirement and metabolic rate during car-
diopulmonary resuscitation: cardiac arrest during exercise. Crit. Care Med. 38,
1760–1761.
Whipp, B.J., Ward, S.A., 1990. Physiological determinants of pulmonary gas exchange
kinetics during exercise. Med. Sci. Sports Exerc. 22, 62–71.
Whipp, B., Ward, S., 1991. Coupling of ventilation to pulmonary gas exchange during
exercise. In: Whipp, B., Wasserman, K. (Eds.), Exercise Pulmonary Physiology
and Pathophysiology, lung biology in health and disease, vol. 52. Marcel Dekker,
New York, pp. 271–307.
Whipp, B., Ward, S., Lamarra, N., Davis, J., Wasserman, K., 1982. Parameters of ventila-
tory and gas exchange dynamics during exercise. J. Appl. Physiol. 52, 1506–1513.
Whipp, B.J., Ward, S.A., Wasserman, K., 1984. Ventilatory responses to exercise and
their control in man. Am. Rev. Respir. Dis. 129, S17–S20.