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J Physiol 0.0 (2024) pp 1–2
1
The Journal of Physiology
OPINION
Death by hypoxia: what were
they thinking?
Vaughan G. Macefield
Department
of
Neuroscience,
Central
Clinical
School,
Monash
University,
Melbourne, Victoria, Australia
Email: vaughan.macefield@monash.edu
Handling Editor: Kim Barrett
The peer review history is available in
the
Supporting
Information
section
of
this
article
(https://doi.org/10.1113/
JP286347#support-information-section).
Alabama
recently
had
the
dubious
distinction of being the first state in
the USA to put someone to death by
inhalation of pure nitrogen through a
face mask. Claiming the judicial killing
of Kenneth Smith on January 25 was a
‘textbook’ execution is galling, considering
what physiologists know about the effects of
hypoxia on the body. Having been on death
row for 33 years, Kenneth Smith was sub-
jected to several attempts in November 2022
to kill him by lethal injection. Officials at
Holman Correctional Facility in Atmore,
Alabama, had tried for 1 h to insert a
cannula into one his veins without success,
even trying to insert a central line, but
abandoned it <1 h before the death warrant
was to expire at midnight. He was back
on death row for another 2 years before
someone had the idea of killing him with
hypoxia. ‘Alabama has done it, and now so
can you’, Mr Marshall, the State’s Attorney
General, said after the execution, with
other states willing to take on this method
of capital punishment (New York Times,
2024).
Notwithstanding my complete opposition
to the death penalty, what were they
thinking
when
considering
death
by
hypoxia? Our bodies are equipped with
specialized chemoreceptors (the carotid
bodies, located at the bifurcation of the
carotid arteries, and the aortic bodies,
located in the aortic arch) that respond to
reductions in blood oxygen. These chemo-
receptors are also sensitive to increases
in CO2 and reductions in pH, as are the
central chemoreceptors located on the
ventral surface of the brainstem, but it is
only the peripheral chemoreceptors that
are able to respond to hypoxia and evoke
the physiologically purposeful responses
that aim to normalize blood O2, increasing
ventilation
and
constricting
peripheral
resistance vessels to ensure delivery of
oxygenated blood to the vital organs,
the heart and brain. Air hunger is the
term often used to describe the dyspnoea
associated with an inability to satisfy the
drive to breathe (Banzett et al., 2021), and
the increased work of breathing is observed
as an increase in respiratory rate and depth,
inward motion of the lower thorax, down-
ward motion of the trachea, nasal flaring
and activation of the accessory muscles
of
inspiration (the sternocleidomastoid
and trapezius muscles); these clinical signs
can be seen in acute respiratory distress
syndrome, chronic obstructive pulmonary
disease and asthma attacks (Santus et al.,
2023). These signs can also be seen with
increased chemical drive to breathe brought
about by hypercapnia and/or hypoxia. It
is known that an increase in arterial CO2
is a stronger stimulus to breathe than a
reduction in inspired O2; marked dyspnoea
is experienced with increases in arterial
PCO2 of only 10 mmHg, whereas reductions
in arterial PCO2 need to be much greater
(40–50 mmHg; the normal partial pressure
of O2 is 160 mmHg) in the presence of
normal CO2 levels (Moosavi et al., 2003).
Nevertheless, the perception of air hunger is
similar to that experienced with normoxic
hypercapnia, suggesting that it is the central
drive to breathe that leads to the dyspnoea
(Moosavi et al., 2003). Indeed, people who
had been pharmacologically paralysed and
artificially ventilated reported increasing air
hunger as inspired CO2 was progressively
increased (the same experiment was not
done for hypoxia), indicating that the
increase in ventilatory movements was not
responsible for the air hunger (Gandevia
et al., 1993). Expansion of the thorax can
alleviate the air hunger to some extent;
rebreathing an asphyxic gas mixture at the
breaking point of an end-expiratory apnoea
relieves the urge to breathe (Fowler, 1954),
and even taking a single breath of pure N2
allows one to continue the apnoea for an
extra 10 s or so (Seitz et al., 2013). But there
is no doubt that breathing pure N2 evokes
air hunger, and this is evidenced by the
increased work of breathing.
The signs of respiratory distress were
recounted by witnesses to the death of
Kenneth Smith, which by all accounts was
a very slow execution (Hedgepeth, 2024).
Strapped tightly to a gurney at the wrists,
with his arms stretched out, and with a
gas mask fixed to his face, at 7.57 pm, as
the N2 was administered through the mask,
‘he began thrashing against the straps, his
whole body and head violently jerking back
and forth for several minutes [and] for
around a minute, [he] began heaving and
retching inside the mask.’ By ∼8:00 pm,
‘Smith’s struggle against the restraints had
lessened, though he continued to gasp for
air. Each time he did so, his body lifted
against the restraints. Smith’s efforts to
breathe continued for several minutes as his
spiritual advisor Jeff Hood prayed nearby,
tears streaming down his face. Around 8:07
pm, Smith made his last visible effort to
breathe’ (Hedgepeth, 2024).
Why choose nitrogen as a means of
killing, particularly given that it had never
been a documented method of capital
punishment? A comparison of euthanasia
of dogs through inhalation of pure N2 with
i.v. injection of pentobarbitone showed that
loss of EEG activity occurred on average
after 36 s (range 33–42 s, n = 4) following
pentobarbitone injection, but after 959 s
(285–2700 s; n = 9) following inhalation of
pure N2 in a sealed chamber; ECG activity
was lost after 250 s (180–300 s) and 1435 s
(660–3900 s) (Quine et al., 1988). Hence,
even in this veterinary setting, in which
animals were presedated, signs of brain
death took 16 min with N2 inhalation, with
cardiac death occurring after 24 min. In
a second study, these authors proceeded
to induce euthanasia with N2 inhalation
in a larger group of cats (n = 63) and
dogs (n = 5) without presedation and
without EEG or ECG monitoring. The
majority collapsed within 60 s (range
13–60 s) of the O2 concentration falling
to 10%, with respiratory arrest (associated
with dilatation and fixation of the pupils)
occurring within 120 s after collapse (Quine
et al., 1988). Convulsions followed the
collapse, with opisthotonos (arching of the
back, extension of the forelimbs and flexion
of the hindlimbs) occurring subsequently,
occasionally accompanied by vocalizations;
opisthotonus occurs towards the end of
hypoxia-induced
apnoea,
immediately
preceding hypoxic gasping (Davis et al.,
1986).
Thus, this execution, the first in which
nitrogen inhalation was used, was not
© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.
DOI: 10.1113/JP286347


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## Page 2

2
Opinion
J Physiol 0.0
humane at all. Respiratory signs of life
disappeared after 10 min, and time of
death was reported as 8:23 pm. Although
consciousness would have been lost well
before hypoxic gasping occurred (a small
experimental study in humans instructed
to hyperventilate with pure N2 revealed
‘clouding of consciousness’ and impaired
vision after 15 s; Ernsting, 1963), there is no
doubt that the extreme hypoxia would have
induced air hunger and stress, particularly
if there was a leak in the mask that allowed
atmospheric O2 to enter.
Physiologists abide by rules to ensure
that euthanasia of experimental animals is
performed humanely; one would hope that
the same treatment is extended to humans.
I plead with physiologists in states of the
USA that uphold the death penalty to speak
to their legislators and insist that death by
hypoxia is never used again.
References
Banzett, R. B., Lansing, R. W., & Binks, A. P.
(2021). Air hunger: A primal sensation and a
primary element of dyspnea. Comprehensive
Physiology, 11(2), 1449–1483.
Davis, P. J., Macefield, G., & Nail, B. S. (1986)
Respiratory muscle activity during asphyxic
apnoea and opisthotonus in the rabbit.
Respiratory Physiology, 65(3), 285–294.
Ernsting, J. (1963). The effect of brief profound
hypoxia upon the arterial and venous oxygen
tensions in man. The Journal of Physiology,
169(2), 292–311.
Fowler, W. S. (1954). Breaking point of
breath-holding. The Journal of Applied
Physiology, 6(9), 539–545.
Gandevia, S. C., Killian, K., McKenzie, D. K.,
Crawford, M., Allen, G. M., Gorman, R. B.,
& Hales, J. P. (1993). Respiratory sensations,
cardiovascular control, kinaesthesia and
transcranial stimulation during paralysis
in humans. The Journal of Physiology, 470,
85–107.
Hedgepeth, L. (2024). https://www.treadbylee.
com/p/never-alone-the-suffocation-of-
kenneth
Moosavi, S. H., Golestanian, E., Binks, A. P.,
Lansing, R. W., Brown, R., & Banzett, R.
B. (2003). Hypoxic and hypercapnic drives
to breathe generate equivalent levels of air
hunger in humans. Journal of Applied Physio-
logy, 94(1), 141–154.
New York Times. (2024). https://www.nytimes.
com/2024/01/26/us/alabama-execution-
kenneth-smith-nitrogen.html
Quine, J. P., Buckingham, W., & Strunin, L.
(1988). Euthanasia of small animals with
nitrogen; comparison with intravenous
pentobarbital. Canadian Veterinary Journal,
29(9), 724–726.
Santus, P., Radovanovic, D., Saad, M., Zilianti,
C., Coppola, S., Chiumello, D. A., &
Pecchiari, M. (2023). Acute dyspnea in the
emergency department: A clinical review.
Internal and Emergency Medicine, 18(5),
1491–1507.
Seitz, M. J., Brown, R., & Macefield, V. G.
(2013). Inhibition of augmented muscle vaso-
constrictor drive following asphyxic apnoea
in awake human subjects is not affected by
relief of chemical drive. Experimental Physio-
logy, 98(2), 405–414.
Additional information
Competing interests
No competing interests declared.
Author contributions
Sole author.
Funding
None.
Keywords
dyspnoea, ethics, euthanasia, hypoxia
Supporting information
Additional supporting information can be found
online in the Supporting Information section
at the end of the HTML view of the article.
Supporting information files available:
Peer Review History
© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.
 14697793, 0, Downloaded from https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP286347 by Goteborgs, Wiley Online Library on [05/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License


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