6157

J Physiol 590.23 (2012) pp 61576165

A key circulatory defence against asphyxia in

infancy the heart of the matter!
Gary Cohen1,2 , Miriam Katz-Salamon2 and Girvan Malcolm1
1
2

Department of Neonatal Medicine, Royal Prince Alfred Hospital, Sydney, Australia

Kvinnors och Barns Halsa, Karolinska Institute, Stockholm, Sweden

Key points
A rise in heart rate boosts cardiac output and blood pressure, improves perfusion and oxygen

delivery, and speeds recovery during an emergency.

The Journal of Physiology

Breathing efforts and lung inflation reflexively elevate heart rate during experimental asphyxia,

and may rescue (auto resuscitate) an animal from imminent death.

We analysed whether this mechanism elevates heart rate when a healthy, sleeping infant is

confronted by mild, progressive asphyxia.

Term-born infants aged 18 days rebreathed the expired gas for short periods to stimulate

breathing and heart rate but not arousal from sleep.

We show that a rising CO2 level during asphyxia is much more strongly cardio-acceleratory

than either vigorous breathing efforts or lung inflation.

This excitatory action of CO2 on the heart develops soon after birth.
We suggest that (i) the hypercapnia during asphyxia helps raise heart rate; (ii) excitation by

respiratory manoeuvres alone is relatively weak and short lived and may not produce the
sustained heart rate rise needed to counteract circulatory depression.

Abstract A resumption of, and escalation in, breathing efforts (hyperpnoea) reflexively
accelerates heart rate (HR) and may facilitate cardiac and circulatory recovery from apnoea. We
analysed whether this mechanism can produce a sustained rise in HR (tachycardia) when a sleeping
infant is confronted by mild, rapidly worsening asphyxia, simulating apnoea. Twenty-seven
healthy term-born infants aged 18 days rebreathed the expired gas for 90 s during quiet sleep to
stimulate breathing and heart rate. To discriminate cardio-excitatory effects of central respiratory
drive, lung inflation, hypoxia, hypercapnia and asphyxia, we varied the inspired O2 level and
compared temporal changes in response profiles as respiratory sensitivity to hypoxia and asphyxia
reset after birth. We demonstrate that asphyxia-induced hyperpnoea and tachycardia strengthen
dramatically over the first week with different time courses and via separate mechanisms. Cardiac
excitation by hypercapnia improves first, followed by a slower improvement in respiratory hypoxic drive. A rise in CO2 consequently elicits stronger, longer lasting tachycardia than moderate
increases in respiratory drive or lung expansion. We suggest that without a strong facilitating action
of CO2 on the immature heart, respiratory manoeuvres may be unable to reflexively counteract
strong vagal bradycardia. This may increase the vulnerability of some infants to apnoea asphyxia.

(Received 17 June 2012; accepted after revision 18 September 2012; first published online 24 September 2012)
Corresponding author G. Cohen: Kvinnors och Barns Halsa, Neonatal Unit, Karolinska Institute, Elevhemmet H1-02,
S-171 76 Stockholm, Sweden. Email: gary.cohen@ki.se


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DOI: 10.1113/jphysiol.2012.239145

6158

G. Cohen and others

J Physiol 590.23

Abbreviations: ALTE, apparent life-threatening episodes of cyanosis; BP, blood pressure; f , breathing rate; F IO2 ,
inspired O2 ; HR, heart rate; P ET,CO2 , end-tidal P CO2 ; QS, quiet sleep; S aO2 , oxygen saturation; SIDS, sudden infant
death syndrome; Tc,O2 , transcutaneous P O2 ; T i and T e , inspiratory and expiratory times; V E , minute volume; V T , tidal
volume; V T /T i , mean inspiratory airflow.

Introduction
Asphyxia the simultaneous lack of O2 (hypoxia) and
increase in CO2 (hypercapnia) in the blood and tissues
initiates a cascade of biochemical events that can rapidly
spiral into irreversible cell damage, circulatory collapse,
coma and death (Gunn et al. 1992; Parer, 1998). It
may develop spontaneously due to cessation of breathing
efforts or complete or partial obstruction of the airway
(Hunt & Brouillette, 1982; Henderson-Smart & Cohen,
1988; Thach et al. 1988; Chiodini & Thach, 1993).
Although reflex defences of humans against progressively
deepening asphyxia are rarely if ever studied, steady-state
simulations reveal they include powerful cardiac and
respiratory excitation to promptly restore O2 delivery
and eliminate toxic CO2 (Lloyd et al. 1958; Brady &
Dunn, 1970; Poulin et al. 1993; Galland et al. 2000).
Various mechanisms and pathways are involved but there
is some convergence and synergy. Strong respiratory drive,
for example, is cardio-acceleratory via central neural
irradiation and lung inflation, so that the deeper and
faster the inspiration the greater the rise in heart rate
(HR) and blood pressure (BP) (Angell-James & Daly, 1978;
Koepchen et al. 1981). In fact, deep convulsive efforts
(gasps) during experimental asphyxia appear to be so
effective in elevating HR and reversing circulatory collapse
that successful auto-resuscitation occurs (Godfrey, 1968;
Angell-James & Daly, 1978). A prompt elevation in HR
(tachycardia) is especially important for survival during
infancy because this is the principal way the immature
heart boosts cardiac output, BP, perfusion and oxygen
delivery during an emergency (Serwer, 1992; Talner et al.
1992; Cohen et al. 2007).
Despite the close interplay between respiratory and
cardiac reflexes shown experimentally, deep breathing
(hyperpnoea) is not always accompanied by tachycardia in real life. Chance recordings from infants who
succumbed to asphyxia reveal that HR remained low
despite well-sustained efforts to gasp (Meny et al. 1994;
Sridhar et al. 2003). Infants who experience apparent
life-threatening episodes of cyanosis (ALTEs) and those
at higher risk of sudden infant death syndrome (SIDS)
also breathe vigorously when stimulated but show no
rise (even a fall) in HR (Katz-Salamon & Milerad, 1998;
Sovik et al. 2001; Edner et al. 2002). Here we addressed
the following questions: (i) Is respiratory drive and/or
lung inflation strongly cardio-acceleratory during infancy?
(ii) Can it elicit the sustained cardiac and circulatory
recovery needed in an emergency? We compared the
reflex effects of mild, progressively deepening asphyxia on

the breathing and HR of healthy, sleeping infants. Our

objectives were to determine whether slight variations
in hyperpnoea produced consistent, sustained rises (or
falls) in HR and whether marked hyperpnoea produced
sustained tachycardia directly via central excitation and/or
indirectly via a lung inflation reflex. We induced hyperpnoea by having infants rebreathe their expired gas for
short periods during sleep (Cohen et al. 1991; Cohen
& Henderson-Smart, 1994). To discriminate effects of
breathing on HR, and between reflex effects due to hypoxia
and hypercapnia separately and together, we administered
three slightly different gases. We also analysed the effects of
different levels of hyperpnoea elicited by the same stimulus
equivalent in a sense to the voluntary paced hyperventilation produced in adults (Bloomfield et al. 2001)
by comparing infants over the first postnatal week.
This period is unique in human development because
the hyperpnoea induced by hypoxia and asphyxia (but
not CO2 ) increases naturally as the carotid body O2
sensors reset (Hertzberg & Lagercrantz, 1987; Carroll &
Kim, 2005). Our hypothesis was that if hyperpnoea is
strongly cardio-acceleratory and drives up HR during
asphyxia, variations produced by both paradigms should
have consistent, sustained effects on HR. If not, it
may be possible to identify physiologically and clinically
important alternative mechanisms that facilitate cardiac
and circulatory recovery.
Methods
The study was approved by the ethics review committee
of Royal Prince Alfred Hospital, and complied with the
Declaration of Helsinki. Informed, signed consent was
obtained from the parents and the attending physician
of all infants.
Subjects were 27 healthy, appropriately grown infants
born at term after uneventful pregnancies, studied
18 days after birth, and stratified into three age
groups (12, 34 and 5 days; Table 1). Only one
infant was studied twice (day 1 and 6). We measured
oxygen saturation from the foot (S aO2 ; Nellcor model
N-100 oximeter in the 3 s mode), transcutaneous (lower
abdomen/post ductal) P O2 (Tc,O2 ; Roche 820 electrode),
end-tidal P CO2 (P ET,CO2 ; Engstrom Eliza sampling at
80 ml min1 ), EEG (vertex mastoid), eye movements
(piezoelectric crystal on the eyelid) and a three-lead ECG.
We also measured tidal volume (V T ), inspiratory and
expiratory times (T i and T e ), breathing rate (f ), minute
volume (V E ) and mean inspiratory airflow (V T /T i , an

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Rebreathing-induced cardio-acceleration during sleep

J Physiol 590.23

Table 1. Population details

Age (days)
Number of infants
Gestation (weeks)
Birth weight (g)
Study weight (g)
V E (ml min1 kg1 )
V T (ml kg1 )
f (breaths min1 )
Heart rate
(beats min1 )
S aO2 (%)
Tc,O2 (torr)
P ET,CO2 (torr)

1.5
12
39
3440
3292
244
5.4
48
112

3.0
6
0.5
39
336 3500
309 3376
26
240
0.9
5.0
10
48
8
112
0.5

98 1
77 8
38 2

6.0
9
0.5
39
240 3465
266 3447
29
215
0.3
5.3
7
43
8
117
0.5

98 2
75 7
40 0.5

1.0
0.7
347
358
36
1.2
8
12

98 1
77 9
43 2

Details of term infants studied, including indices of respiratory

performance at rest (quiet sleep, breathing room air).
Abbreviations: V E , minute volume; V T , tidal volume; f,
breathing rate; S aO2 , arterial O2 saturation; Tc,O2 , transcutaneous P O2 ; P ET,CO2 , end-tidal P CO2 . Data are means SD;
P < 0.05 (ANOVA). 1 torr = 133.3 Pa.

index of central respiratory drive; Moriette et al. 1985;

Tobin et al. 1988) with a nasal mask pneumotachograph
connected to a differential pressure transducer (MP-45;
Validyne Engineering, Northridge, CA, USA). The device
was calibrated at the start and end of the study; linear
interpolation minimized error arising from drift (Cohen
et al. 1991). Infants lay supine and testing was confined

6159

to quiet sleep (QS; trace-alternant EEG pattern, regular

breathing movements, absences of eye and gross body
movements except for brief startles) (Prechtl, 1974). Three
rebreathing gases were administered: 57% CO2 in air
(21% O2 ), or 40 or 15% O2 , referred to as normoxia,
hyperoxia and asphyxia, respectively. Supplemental O2
was added to the rebreathing circuit at 7 ml min1 kg1
and titrated via a low-flow meter to maintain pre-test
S aO2 /Tc,O2 (normoxia), or allow it to fall slowly (asphyxia).
Asphyxia was terminated at S aO2 = 85% (Fig. 1). Tests
lasted 1.52 min and were terminated before arousal; if
arousal did occur we abandoned the test and waited for
the next QS epoch before resuming. At least 5 min elapsed
between tests to return to baseline. The order of gases
was alternated and counterbalanced across infants/sleep
epochs until 35 responses were obtained at each inspired
O2 (F IO2 ), which required several hours/epochs.
We excluded tests complicated by state transitions or
arousal (decrease in EEG voltage or movement artefacts
3 s on two or more channels). Baseline was 30 s preceding each test. The initial 2530 s of rebreathes, during
which CO2 in the bag and lung equilibrated, was excluded.
We calculated breath-by-breath V T , f , V E (=V T f )
and V T /T i . The ventilatory response was the slope of
the line relating each parameter (abscissa) to P ET,CO2
using least squares regression (Fig. 2A). Rates of rise/fall
in P ET,CO2 /S aO2 were also determined by regression. We
accounted for the 8 s lag between S aO2 and Tc,O2 (Cohen
et al. 1991). The HR change was the mean RR (inter-beat)

Figure 1. Rebreathing during sleep

During mild asphyxia, end-tidal P CO2 (P ET,CO2 ) rose and arterial saturation (SaO2 )/transcutaneous O2 (Tc,O2 ) fell
slowly over 2 min (A). Stimuli delivered by the three protocols are compared (BD; means SD for day 6).

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G. Cohen and others

interval measured 8090 s after the rebreathe started,

expressed as percentage baseline.
We assumed (for simplicity) that effects of asphyxia
could be partitioned into a component due to CO2
and another to an interaction effect of hypoxia, and
furthermore, that: (i) CO2 stimulates mainly the central
chemoreceptors and the small peripheral contribution is
negligible in hyperoxia (Lloyd et al. 1958); (ii) hypoxia
stimulates mainly the peripheral chemoreceptors and adds
to existing central CO2 drive (St Croix et al. 1996; Mohan
& Duffin, 1997); and (iii) the peripheral contribution
(hypoxic drive) is estimated by subtracting (i) from (ii).
Each subject served as his/her own control to adjust for
inter-individual variation between the absolute magnitude
of responses, as follows:
Hypoxic drive = [(asphyxia response

J Physiol 590.23

entirely to CO2 drive; the greater the difference, the greater

is the contribution of hypoxic drive: if hypoxic drive = 100
then CO2 and hypoxic drive contribute equally to the
asphyxia response.

Statistics

Replicates were averaged for each subject and then pooled

to generate mean responses at each age. We used a
two-factor ANOVA to test for the effects of (i) F IO2 (ii)
age or (iii) F IO2 by age (interaction) effects, followed
by pairwise t tests (with Bonferroni correction) if the
omnibus ANOVA was significant (P 0.05).
Results

normoxia response)

Breathing

/normoxia response] 100

Basal (resting) breathing pattern asleep did not change

over the first week but P ET,CO2 levels rose (Table 1).
Consequently, the position of all ventilatory response
curves shifted slowly rightwards (Fig. 2A). Stimuli

Thus, if the asphyxia equals the normoxia response, then

hypoxic drive = 0 and the response can be attributed

Figure 2. Rebreathing-induced hyperpnoea.

Representative breath-by-breath plots of end-tidal CO2 (P ET,CO2 ) vs. minute volume (V E ) for an infant studied
twice (A; for clarity, only asphyxia and normoxia data/regression lines are shown). The V E responses were initially
comparable (parallel slopes) but by day 6 the asphyxia slope (continuous lines) was steeper. Note the rightward
shift in position of the curves with age. Mean ( SD) slopes of central respiratory drive (V T /T i ; B), V E (C) and tidal
volume (V T ; D) vs. P ET,CO2 lines are compared ( P < 0.05 vs. all other tests at all ages). Asphyxia elicited stronger
drive and volume responses on day 6 (black arrows) due to increased sensitivity to hypoxia (labelled 1 in B) with
no change in sensitivity to CO2 per se (grey arrows; labelled 2 in B). 1 torr = 133.3 Pa.

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Rebreathing-induced cardio-acceleration during sleep

J Physiol 590.23

Table 2. Rebreathing protocols

Normoxia Hyperoxia
Asphyxia
(57% (57% CO2 + (57% CO2 +
40% O2 )
15% O2 )
CO2 +air)
No. of tests
Start-P ET,CO2
(torr)
End-P ET,CO2
(torr)
P ET,CO2
(torr min1 )
End-S aO2 (%)
S aO2 (% min1 )
End-Tc,O2 (torr)
Duration (s)

76
51 4

74
52 4

71
52 4

0.59

58 4

59 5

57 5

0.12

5.7 1

5.8 0.4

5.1 1.5

0.001

94
0.8
74
70

3
97 3
86 3
3II 0.5 2 10 4II
8
96 13
57 6

67 9
61 11
4

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Tachycardia was slightly, consistently enhanced by

asphyxia and attenuated by hyperoxia, to the same extent
at each age (Fig. 3A and B). Thus, CO2 (but not hypoxia)
becomes a stronger cardiac stimulant soon after birth the
reverse of the situation for breathing (Fig. 3C and D).
Discussion
Tachycardia is how a neonate, with limited myocardial
reserve and compliance, boosts cardiac output and BP
under stress (Serwer, 1992; Talner et al. 1992; Cohen et al.

0.001
0.001
0.001
0.001

The hypercapnia ramp was fixed (similar CO2 levels at the

start and end of each protocol, and similar rates of rise (rows
24); S aO2 /Tc,O2 was kept constant (normoxia), raised (hyperoxia) or lowered (asphyxia) (rows 57). Differences between
hyperpnoea and heart rate thus reflected principally variable
input from the peripheral (O2 ) chemoreceptors. For technical
reasons asphyxia tests were slightly shorter in duration and
the rise in CO2 slightly less. Abbreviations: start/end-P ET,CO2 ,
end-tidal CO2 at start/end rebreathe; P ET,CO2 , rate of rise
during rebreathe; end-S aO2 , arterial turation at end rebreathe;
S aO2 , rate of change of S aO2 ; end-Tc,O2 , transcutaneous
P O2 at end rebreathe; duration excludes initial equilibration
period. Data are means SD for all ages combined; common
superscripts on each line denote significant differences
(ANOVA). 1 torr = 133.3 Pa.

administered by the three protocols were otherwise highly

consistent (Fig. 1B-D and; Table 2; see also supplementary
Table 1). All rebreathing protocols produced comparable
increases in inspiratory drive and volumes before day 3.
As anticipated, inspiratory drive and volume responses to
asphyxia increased significantly by day 6 (50 and 40%,
respectively), due to deeper, faster breathing (V T and
f responses were also 22 and 28% greater, respectively)
(Fig. 2BD). This change largely (although perhaps not
exclusively) reflects resetting of peripheral sensitivity to
hypoxia (Hertzberg & Lagercrantz, 1987; Pepper et al.
1995).
Heart rate

A 56 torr min1 (0.670.8 kPa min1 ) rise in P ET,CO2

over 2 min had little effect on HR 12 days after
birth but elicited pronounced tachycardia by day 3
(Fig. 3A). Tachycardia was similar on day 6, irrespective
of the extent of hyperpnoea (Fig. 2C) or central drive
(Fig. 2B). Thus, bigger/faster inflations and stronger
central drive produced no additional cardio-acceleratory
effect over and above that due to CO2 several days earlier.

Figure 3. Rebreathing-induced tachycardia.

The rebreathing-evoked rise in heart rate (HR; percentage change
from baseline) increased significantly by day 3 with no change
subsequently, indicating that it was due to improved cardiac CO2
sensitivity (shown by the grey arrow labelled 1 in A). Tachycardia was
slightly augmented by a fall in O2 (the asphyxianormoxia difference
labelled 2 in A; equal to cardiac hypoxic drive) and attenuated by a
rise in O2 (the normoxiahyperoxia difference labelled 3 in A); these
differences are expanded to illustrate that effects of hypoxia and
hyperoxia on the heart did not change with age (B). Omnibus P
values (ANOVA) are shown in A; only the asphyxiahyperoxia
differences were significant in post hoc tests (indicated for clarity in
B: P < 0.05 for the same age), which means that large changes in
oxygenation were required to marginally augment/attenuate HR.
Hypoxic cardiac (C) and ventilatory drive (D) is also shown for each
infant to illustrate how the latter strengthened progressively with
age (r 2 is the correlation coefficient).


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G. Cohen and others

2007). Here we show that moderate-intensity fast, deep

breathing is not the main cause of reflex tachycardia when
a sleeping infant is confronted by deepening asphyxia. We
suggest that other mechanisms resist and restrain cardiac
and circulatory collapse during such a crisis and one we
identified is a powerful cardio-acceleratory action of rising
CO2 levels.
HR reflects a balance between vago-sympathetic drive;
an increase in the former and/or withdrawal of the latter
lowers HR and vice versa (Daly & Scott, 1963; Spyer,
1994). Although hypoxia, CO2 and asphyxia all elicit
generalized sympathetic activation that accelerates adult
HR (Sechzer et al. 1960; Morgan et al. 1995), differences
may manifest early in life as competing reflex effects on HR
are unmasked. The primary cardiac response to hypoxia is
vagal excitation and sympathetic withdrawal, which in the
fetus produces an absence of breathing efforts, the classic
diving response bradycardia (Daly et al. 1979; Butler &
Jones, 1997; Foster & Sheel, 2005). After birth, however,
hypoxia also stimulates breathing, which excites stretch
receptors in the lungs and thorax. These send inhibitory
projections to cardiac vagal motor neurones exerting
tonic inhibitory control over HR. Consequently, breathing
within the normal range of tidal volumes invariably
elevates (via this secondary mechanical reflex) neonatal
HR and can wholly or partially reverse vagal bradycardia.
During hyperpnoea, excitatory irradiation (spill over)
from central inspiratory neurones in close proximity
further antagonizes the cardio-vagal motor neurones,
which amplifies the tachycardia; the two mechanisms
explain in part why HR waxes and wanes in rhythm
with breathing (Downing et al. 1962; Daly et al. 1979;
Koepchen et al. 1981; Isaacson, 2000). We found, however,
that central drive and lung inflation were not strongly
coupled to HR during sleep in infancy when averaged
over breath cycles, even though the inflation reflex itself
may be quite strong (Hassan et al. 2001). Modulation
of the human cardiac cycle by mechanical (including
baroreceptor) inputs may in fact be weak for good
reason: it varies within the breath cycle, is strongest
during inspiration and weakens during expiration, and
may even disappear completely during hyperpnoea,
when HR becomes constant (Angelone & Coulter, 1964;
Schafer et al. 1998; Clark et al. 2012). The sustained
HR rise needed to boost BP, perfusion, O2 delivery
and rescue an infant in danger must clearly originate
elsewhere.
CO2 also has competing cardiovascular actions. On the
one hand it depresses the vasomotor centre and the myocardium, dilates the blood vessels, and lowers HR and
BP (Shoemaker et al. 2002). But it also elicits strong
adrenal and cardiac sympathetic nerve catecholamine
release, which elevates HR and BP (Sechzer et al. 1960;
Downing et al. 1971). An 18 torr (2.4 kPa) rise in CO2
elevates HR by 10% and BP by at least as much (Cohen

J Physiol 590.23

et al. 2008), yet the equivalent fall in P O2 (10% fall in

S aO2 ) has no additional effect (Fig. 3). This arrangement
may help protect the heart against the notoriously labile
O2 supply in infancy and avoid undesirable fluctuations
in perfusion (Henderson-Smart, 1980). The same level of
hypoxia does however augment hyperpnoea once the peripheral chemo reflex resets (Fig. 2A). A large rise in P O2
(40 torr; 5.3 kPa) on the other hand attenuates cardiac
excitability slightly (Table 2 and Fig. 3B); this could be a
direct effect of O2 on the myocardium, or due to alterations
in brain vago-sympathetic outflow, which varies with
F IO2 during CO2 breathing (Daly & Bondurant, 1962;
Teppema et al. 1997). As we found previously (Cohen &
Henderson-Smart, 1994) hyperoxia had no clear effect on
breathing even on day 6 when it silences the peripheral
chemo reflex (Hertzberg & Lagercrantz, 1987). The reason
may be that a high F IO2 stimulates neonatal metabolism; if
so, increased tissue CO2 production could heighten central
respiratory drive enough to compensate for loss of peripheral drive (Mortola et al. 1992a). The point is: rising CO2
levels exert faster and stronger actions on the heart than
do declining O2 levels. Moreover, and more importantly,
the balance normally shifts towards excitation and away
from depression quite soon after birth, partly reflecting
rapid changes in neurotransmitter and adrenergic receptor
synthesis, release and expression (Lagercrantz & Marcus,
1992; Talner et al. 1992)

Cardiac auto-resuscitation

In severe asphyxia, hyperpnoea is followed by primary

apnoea then agonal gasping and, finally, terminal
apnoea (Godfrey, 1968). Successful auto-resuscitation
once primary apnoea ensues requires two things to
happen: (i) a resumption of breathing efforts (gasping)
to inflate and oxygenate the lungs, and (ii) a sustained rise
in HR, cardiac output and BP to re-oxygenate the blood
and re-perfuse the heart and brain. Hypercapnia-induced
cardio acceleration may be especially important in such
situations because: (i) CO2 levels rise rapidly in infancy
due to the fast metabolic rate nearly two-fold greater
(weight corrected) than in the adult (Henderson-Smart
& Cohen, 1988; Mortola et al. 1992b), and (ii) it helps to
restrain vagal slowing of the heart, which is accentuated
by hypoxia and sleep generally. Our simulations were
performed in a healthy cohort. We estimate that a week-old
infant exposed to mild progressive asphyxia breathes about
35% faster (4358 breaths min1 ), doubles breath volume
(from 19 to 40 ml) and triples minute volume (from
752 to 2290 ml min1 ) over resting levels. These are substantial increases equivalent to moderate exercise bearing
in mind the infants remained asleep. We do not claim
that modulation of cardio-vagal or sympathetic drive is
unaffected by more dramatic escalations in breathing,

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J Physiol 590.23

Rebreathing-induced cardio-acceleration during sleep

only that effects on the heart in real-life situations may

be considerably overestimated (Schafer et al. 1998; Clark
et al. 2012).
Limitations

We could not extend the age range, record BP or

vary posture all factors that influence cardiovascular
control during infancy (Cohen et al. 2012). Infants who
succumb to asphyxia generally do so later (SIDS peaks at
13 months) whilst sleeping prone. Our study, however,
must be seen first and foremost in the context of a
specific hypothesis, for which the ages and method chosen
were crucial: changes in chemo receptor and breathing
drives are most profound and informative during the
first postnatal week. For reasons of propriety and to
conform to parents wishes and ward routine we did not
(with one exception) study each infant more than once
or at precisely defined times after birth. Our technique
produces relatively intense ramps that simulate central
or obstructive apnoea, rather than the slow positional
asphyxia that may develop sleeping face down in soft
bedding (Chiodini & Thach, 1993). Its advantages are
speed and accuracy: ventilatory sensitivity is sleep state
specific and largely uninfluenced by variations in cerebral
blood flow (Cohen et al. 1991; Mohan et al. 1999). Other
methods fail to produce true asphyxia arterial CO2 rises
to 45 torr (6 kPa) and S aO2 falls <1% (Campbell et al.
2001) (see Table 2) and may be confounded by the
potent vasodilator/constrictor actions of hypoxia-CO2 /O2
(Rigatto et al. 1975; Leahy et al. 1980). Throughout this
report we have used hypoxic drive to refer to the peripheral contribution to drive, which we acknowledge is
a simplification. As the peripheral chemoreceptors also
respond to CO2 , maturation may involve changes in the
way hypoxia and CO2 are sensed/interact within these
structures (Pepper et al. 1995). Finally, the slope of the
V E response to asphyxia is initially linear (Fig. 2A) but
the entire curve is hyperbolic, so extrapolating from mild
(which we administered) to profound asphyxia is not
accurate (Rebuck & Slutsky, 1981). Moreover, at some
point profound asphyxia usually triggers gasping and
intense, tonic and inspiratory-synchronous sympathetic
excitation (Solomon, 2000); the relevance of our findings
to such extreme behaviour or failure to auto resuscitate is
consequently uncertain. The mechanism we identify could
contribute to an unresponsive heart and stubbornly low
HR during gasping, but there are others (Deshpande et al.
1999).
Implications

Extreme events in infancy do not develop suddenly but

slowly over several hours (Hunt et al. 2008). Slowly
developing hypercapnia (like hypoxia) is a notoriously

6163

weak respiratory stimulant (Gozal et al. 1994; Cohen

et al. 1997). If the mechanism we describe fails to
develop soon after birth, strong vagal depression of
the heart may be much more difficult to reverse by
excitatory (including respiratory) manoeuvres. Infants
who experience ALTEs as well as infants of smokers
(who are most at risk of SIDS) may be especially
vulnerable because their tachycardia response to CO2 is
weak to absent, despite a normal ventilatory response
(Katz-Salamon & Milerad, 1998; Sovik et al. 2001). For the
majority who survive, back-up mechanisms presumably
compensate adequately most of the time (there may still be
long-term consequences independent of mortality). The
real danger from asphyxia may come when the cardiac and
back-up excitatory mechanisms are weakened (McCulloch
et al. 1982; Carpenter et al. 2004; Franco et al. 2011).
Conclusion

The immature heart remains insensitive to falling blood O2

but becomes much more excited by rising blood CO2 soon
after birth. This facilitating action of CO2 helps to elevate
HR, boost BP, perfusion and O2 delivery, and counteract
circulatory collapse during asphyxia.
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Author contributions
G.C. designed the study; G.C. and G.M. performed the research;
M.K-S. contributed analytical tools; G.C and M.K-S. analysed
the data; G.C. wrote the paper. All authors reviewed and
approved the final published version of the manuscript. These
studies were undertaken at the Neonatal unit at Royal Prince
Alfred Hospital (Sydney). The authors declare no conflicts of
interest.

Acknowledgements
We are indebted to David Henderson-Smart for original ideas
and suggestions. The study was supported by grants from Goesta
Fraenkel Foundation, The National Health and Medical Research
Council of Australia and the Financial Markets Foundation for
Children.


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