tions: one of metabolism and the other be-
havioral. Metabolically, respiratory control is
directed principally at maintaining tissue oxy-
genation and normal acid-base balance. It is
regulated mainly by reflex neural mechanisms
located in the posterior-dorsal region of the
pons and in the medulla. Behavioral control
of breathing allows it to be integrated with
swallowing, and in humans, with verbal and
emotional communication as well as other
behaviors.
Respiratory rhythm is an intrinsic property
of the brainstem that is generated by a network
of neurons that lie in the ventrolateral medulla,
including the pre-Bo¨tzinger complex
29,30
(see
Figure 2–3). This rhythm is regulated in the
intact brain by a number of influences that
enter via the vagus and glossopharyngeal nerves.
ACh
Medulla
Midbrain
Spinal Cord:
Muscarinic
ACh
ACh
T2-T12: Intercostal Motor Neurons
C3-5: Phrenic Motor Nucleus
Hypoglossal Motor Nucleus
Nicotinic
IX and X Nerves
Cervical
Thoracic
Lumbar
Sacral
Cortex
Prefrontal
Cortex
Hypothalamus
Ventral
Respiratory Group
Parabrachial Nucleus
2 adrenergic
NE
T2-8
Pons
Nucleus
Ambiguus
Figure 2–4. A diagram summarizing the respiratory control pathways in the brain. Afferents from the lung (pulmonary
stretch), upper airway (cough reflexes), and carotid body arrive via cranial nerves IX and X in the nucleus of the solitary tract
(gray), also called the dorsal respiratory group. These control airway and respiratory reflexes, analogous to the cardiovas-
cular system, by inputs to the ventrolateral medulla. These include outputs to the airways via the vagus nerve (red) and
outputs from the ventral respiratory group (orange) to the spinal cord, controlling sympathetic airway responses (green)
and respiratory motor (phrenic motor nucleus, blue) and accessory motor (hypoglossal and intercostal, blue) outputs. The
ventral respiratory group is responsible for generating respiratory rhythm. However, it is assisted in this process by the
parabrachial nucleus (or pontine respiratory group, purple), which receives ascending respiratory afferents and integrates
them with other brainstem reflexes (e.g., swallowing). The prefrontal cortex (brown) provides behavioral regulation of
breathing, producing a continual breathing rhythm even in the absence of metabolic need. This influences the hypothal-
amus (light green), which may vary respiratory pattern in coordination with behavior or emotion. ACh, acetylcholine; NE,
norepinephrine.
48
Plum and Posner’s Diagnosis of Stupor and Coma
The carotid sinus branch of the glossopharyn-
geal nerve brings afferents that carry informa-
tion about blood oxygen and carbon dioxide
content, whereas the vagus nerve conveys pul-
monary stretch afferents. These terminate in
the commissural, ventrolateral, intermediate,
and interstitial components of the nucleus of
the solitary tract.
31–33
Chemoreceptor affer-
ents can increase respiratory rate and depth,
whereas pulmonary stretch receptors tend to
inhibit lung inflation (the Herring-Breuer re-
flex). These influences are relayed to reticular
areas in the ventrolateral medulla that regulate
the onset of inspiration and expiration.
34
In
addition, serotoninergic neurons in the ventral
medulla may also serve as chemoreceptors and
directly influence the nearby circuitry that gen-
erates the respiratory rhythm.
35,36
The medullary circuitry that controls respira-
tion is under the control of pontine cell groups
that integrate breathing with ongoing orofacial
stimuli and behaviors.
37
Neurons in the para-
brachial nucleus primarily increase the rate
and depth of respiration, presumably in rela-
tion to emotional responses or in anticipation
of metabolic demand during various behaviors.
On the other hand, neurons located more ven-
trally in the intertrigeminal zone, between the
principal sensory and motor trigeminal nuclei,
produce apneas, which are necessary during
swallowing and in response to noxious chemi-
cal irritation of the airway (e.g., smoke or water
in the nasal passages).
38
Superimposed upon these metabolic de-
mands and basic reflexes, the forebrain can com-
mand a wide range of respiratory responses.
Respiration can be altered by emotional re-
sponse, and it increases in anticipation of met-
abolic demand during voluntary exercise, even
if the muscle that is to be contracted has been
paralyzed (i.e., as a consequence of central
command rather than metabolic reflex). The
pathways that control vocalization in humans
appear to originate in the frontal opercular cor-
tex, which provides premotor and motor inte-
gration of orofacial motor actions. However,
there is also a prefrontal contribution to the
maintenance of respiratory rhythm, even in the
absence of metabolic demand (the basis for
posthyperventilation apnea, described below).
These considerations make the recognition
of respiratory changes useful in the diagnosis of
coma (Figure 2–5).
POSTHYPERVENTILATION APNEA
If the arterial carbon dioxide tension is low-
ered by a brief period of hyperventilation, a
healthy awake subject will nevertheless con-
tinue to breathe with a normal rhythm, at least
initially,
39
albeit at reduced volume, until the
PCO
2
returns to its original level. By contrast,
subjects with diffuse metabolic impairment of
the forebrain, or bilateral structural damage to
the frontal lobes, commonly demonstrate post-
hyperventilation apnea.
40
Their respirations
stop after deep breathing has lowered the car-
bon dioxide content of the blood below its usual
resting level. Rhythmic breathing returns when
endogenous carbon dioxide production raises
the arterial level back to normal.
The demonstration of posthyperventilation
apnea requires that the patient voluntarily take
several deep breaths, so that it is useful in dif-
ferential diagnosis of lethargic or confused pa-
tients, but not in cases of stupor or coma. One
instructs the subject to take five deep breaths.
No other instructions are given. It is useful
for the examiner to place a hand on the pa-
tient’s chest, to make it easier later to detect
when breathing has restarted, and to count
the breaths. If the lungs function well, the ma-
neuver usually lowers the arterial carbon di-
oxide by 8 to 14 torr. At the end of the deep
breathing, wakeful patients without brain dam-
age show little or no apnea (less than 10 sec-
onds). However, in patients with forebrain im-
pairment, the period of apnea may last from 12
to 30 seconds. The neural substrate that pro-
duces a continuous breathing pattern even in
the absence of metabolic need is believed to
include the same frontal pathways that regu-
late behavioral alterations of breathing patterns,
as the continuous breathing pattern disappears
with sleep, bilateral frontal lobe damage, or dif-
fuse metabolic impairment of the hemispheres.
CHEYNE-STOKES RESPIRATION
Cheyne-Stokes respiration
41
is a pattern of
periodic breathing with phases of hyperpnea
alternating regularly with apnea. The depth
of respiration waxes from breath to breath in a
smooth crescendo during onset of the hyper-
pneic phase and then, once a peak is reached,
wanes in an equally smooth decrescendo until a
period of apnea, usually from 10 to 20 seconds,
Examination of the Comatose Patient
49