Professional Documents
Culture Documents
A Key Circulatory Defence Against Asphyxia in Infancy - The Heart of The Matter!
A Key Circulatory Defence Against Asphyxia in Infancy - The Heart of The Matter!
A Key Circulatory Defence Against Asphyxia in Infancy - The Heart of The Matter!
Key points
A rise in heart rate boosts cardiac output and blood pressure, improves perfusion and oxygen
Breathing efforts and lung inflation reflexively elevate heart rate during experimental asphyxia,
We analysed whether this mechanism elevates heart rate when a healthy, sleeping infant is
Term-born infants aged 18 days rebreathed the expired gas for short periods to stimulate
We show that a rising CO2 level during asphyxia is much more strongly cardio-acceleratory
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
C 2012 The Authors. The Journal of Physiology
C 2012 The Physiological Society
DOI: 10.1113/jphysiol.2012.239145
6158
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
J Physiol 590.23
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
6159
6160
J Physiol 590.23
Statistics
normoxia response)
Breathing
J Physiol 590.23
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
6161
0.001
0.001
0.001
0.001
C 2012 The Authors. The Journal of Physiology
C 2012 The Physiological Society
6162
J Physiol 590.23
Cardiac auto-resuscitation
J Physiol 590.23
6163
C 2012 The Authors. The Journal of Physiology
C 2012 The Physiological Society
6164
Clark MT, Rusin CG, Hudson JL, Lee H, Delos JB, Guin LE,
Vergales BD, Paget-Brown A, Kattwinkel J, Lake DE &
Moorman JR (2012). Breath-by-breath analysis of
cardiorespiratory interaction for quantifying developmental
maturity in premature infants. J Appl Physiol 112, 859867.
Cohen G & Henderson-Smart DJ (1994). The reproducibility
of the response of the human newborn to CO2 measured by
rebreathing and steady-state methods. J Physiol 476,
355363.
Cohen G, Lagercrantz H & Katz-Salamon M (2007). Abnormal
circulatory stress responses of preterm graduates. Pediatr Res
61, 329334.
Cohen G, Malcolm G & Henderson-Smart D (1997). A
comparison of the ventilatory response of sleeping newborn
lambs to step and progressive hypoxaemia. J Physiol 503,
203213.
Cohen G, Vella S, Jeffery H, Lagercrantz H & Katz-Salamon M
(2008). Cardiovascular stress hyperreactivity in babies of
smokers and in babies born preterm. Circulation 118,
18481853.
Cohen G, Vella S, Jeffery H, Lagercrantz H & Katz-Salamon M
(2012). Positional circulatory control in the sleeping infant
and toddler: role of the inner ear and arterial pulse pressure.
J Physiol 590, 34833493.
Cohen G, Xu C & Henderson-Smart D (1991). Ventilatory
response of the sleeping newborn to CO2 during normoxic
rebreathing. J Appl Physiol 71, 168174.
Daly MD, Angell-James JE & Elsner R (1979). Role of
carotid-body chemoreceptors and their reflex interactions in
bradycardia and cardiac arrest. Lancet 1, 764767.
Daly MD & Scott MJ (1963). The cardiovascular responses to
stimulation of the carotid body chemoreceptors in the dog. J
Physiol 165, 179197.
Daly WJ & Bondurant S (1962). Effects of oxygen breathing on
the heart rate, blood pressure, and cardiac index of normal
menresting, with reactive hyperemia, and after atropine. J
Clin Invest 41, 126132.
Deshpande P, Khurana A, Hansen P, Wilkins D & Thach BT
(1999). Failure of autoresuscitation in weanling mice:
significance of cardiac glycogen and heart rate regulation. J
Appl Physiol 87, 203210.
Downing SE, Campbell AG, Rocamora JM & Talner NS (1971).
Influences of hypercapnia on cardiac function in the
newborn lamb. Yale J Biol Med 43, 242256.
Downing SE, Remensnyder JP & Mitchell JH (1962).
Cardiovascular responses to hypoxic stimulation of the
carotid bodies. Circ Res 10, 676685.
Edner A, Ericson M, Milerad J & Katz-Salamon M (2002).
Abnormal heart rate response to hypercapnia in boys with an
apparent life-threatening event. Acta Paediatr 91,
13181323.
Foster GE & Sheel AW (2005). The human diving response, its
function, and its control. Scand J Med Sci Sports 15, 312.
Franco P, Montemitro E, Scaillet S, Groswasser J, Kato I, Lin JS
& Villa MP (2011). Fewer spontaneous arousals in infants
with apparent life-threatening event. Sleep 34, 733743.
Galland BC, Bolton DP, Taylor BJ, Sayers RM & Williams SM
(2000). Ventilatory sensitivity to mild asphyxia: prone versus
supine sleep position. Arch Dis Child 83, 423428.
J Physiol 590.23
C 2012 The Authors. The Journal of Physiology
C 2012 The Physiological Society
J Physiol 590.23
6165
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.
C 2012 The Authors. The Journal of Physiology
C 2012 The Physiological Society