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medulla.28 In addition, the nucleus of the solitary tract provides both direct and relayed excitatory inputs to the cardiac decelerator neurons in the nucleus ambiguus.27 Thus, a rise in blood pressure results in a reflex fall in heart rate and vasomotor tone, re-establishing a normal arterial pressure. Conversely, a fall in blood pressure causes a reflex tachycardia and vasoconstriction, re-establishing the necessary arterial perfusion pressure. As a result, on assuming an upright posture, there is normally a small increase in both heart rate and blood pressure.

On occasion, loss of consciousness may result from failure of this baroreceptor reflex arc. In such patients, measurement of standing and supine blood pressure and heart rate discloses a fall in blood pressure on assuming an upright posture that is clinically associated with symptoms of insufficient CBF. Rigid criteria for diagnosing orthostatic hypotension (e.g., a fall in blood pressure of 10 or 15 mm Hg) are not useful, as systemic arterial pressure is usually measured in the arm but the symptoms are produced by decreased blood flow to the brain. A pressure head that is adequate to perfuse the arm (which is at the same elevation as the heart) will be reduced by 15 to 23 mm Hg at the brain in an upright posture, and if perfusion pressure to the brain falls even a few mm Hg below the level needed to maintain autoregulation, the drop in cerebral perfusion may be precipitous.

The most common nonneurologic causes of orthostatic hypotension, including low intravascular volume (often a consequence of diuretic administration or inadequate fluid intake), cardiac pump failure, and medications that impair arterial constriction (e.g., alpha blockers or direct vasodilators), do not impair the tachycardic response. Most neurologic cases of orthostatic hypotension, including peripheral autonomic neuropathy or central or peripheral autonomic degeneration, impair both the heart rate and the blood pressure responses. Put in other words, the hallmark of baroreceptor reflex failure is absence of the elevation of heart rate when arterial pressure falls in response to an orthostatic challenge.

Respiration

The brain cannot long survive without an adequate supply of oxygen. Within seconds of

being deprived of oxygen, brain function begins to fail, and within minutes neurons begin to die. The physician must ensure that respiration is supplying adequate oxygenation. To do this requires examination of both respiratory exchange and respiratory pattern. Listening to the chest will ensure that there is adequate movement of air. A normal patient at rest will regularly breathe at about 14 breaths per minute and the exchange of air can be heard at both lung bases. The physician should estimate from the rate and depth of respiration whether the patient is hypoor hyperventilating or whether respiration is normal. The patient’s color is a gross indicator of oxygenation: cyanosis indicates deficient oxygenation; a cherry red color may also indicate deficient oxygenation because of CO intoxication. A better estimate of oxygenation can be achieved by placing an oximeter on the finger; many intensive care units and some emergency departments also measure expired CO2, which correlates well with PCO2.

This section considers the neuroanatomic basis of respiratory abnormalities that accom-

Table 2–2 Neuropathologic Correlates

of Breathing Abnormalities

Forebrain damage

Epileptic respiratory inhibition

Apraxia for deep breathing or breath holding ‘‘Pseudobulbar’’ laughing or crying Posthyperventilation apnea

Cheyne-Stokes respiration Hypothalamic-midbrain damage

Central reflex hyperpnea (neurogenic pulmonary edema)

Basis pontis damage

Pseudobulbar paralysis of voluntary control Lower pontine tegmentum damage or

dysfunction Apneustic breathing Cluster breathing

Short-cycle anoxic-hypercapnic periodic respiration

Ataxic breathing (Biot) Medullary dysfunction

Ataxic breathing

Slow regular breathing

Loss of autonomic breathing with preserved voluntary control

Gasping

pany coma (Table 2–2, Figure 2–3). Chapter 5 discusses respiratory responses to metabolic disturbances. Because neurogenic and metabolic influences on breathing interact extensively, respiratory changes must be interpreted cautiously if there is evidence of pulmonary disease.

The pattern of respiration can give important clues concerning the level of brain damage. Once assured that there is adequate exchange of oxygen, the physician should watch

the patient spontaneously breathe. Irregularities of the respiratory pattern that provide clues to the level of brain damage are described in the paragraphs below.

PATHOPHYSIOLOGY

Breathing is a sensorimotor act that integrates nervous influences arising from nearly every level of the brain and upper spinal cord. In humans, respiration subserves two major func-

tions: one of metabolism and the other behavioral. Metabolically, respiratory control is directed principally at maintaining tissue oxygenation 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 complex29,30 (see Figure 2–3). This rhythm is regulated in the intact brain by a number of influences that enter via the vagusand glossopharyngeal nerves.

The carotid sinus branch of the glossopharyngeal nerve brings afferents that carry information about blood oxygen and carbon dioxide content, whereas the vagus nerve conveys pulmonary stretch afferents. These terminate in the commissural, ventrolateral, intermediate, and interstitial components of the nucleus of the solitary tract.31–33 Chemoreceptor afferents can increase respiratory rate and depth, whereas pulmonary stretch receptors tend to inhibit lung inflation (the Herring-Breuer reflex). 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 generates the respiratory rhythm.35,36

The medullary circuitry that controls respiration is under the control of pontine cell groups that integrate breathing with ongoing orofacial stimuli and behaviors.37 Neurons in the parabrachial nucleus primarily increase the rate and depth of respiration, presumably in relation to emotional responses or in anticipation of metabolic demand during various behaviors. On the other hand, neurons located more ventrally in the intertrigeminal zone, between the principal sensory and motor trigeminal nuclei, produce apneas, which are necessary during swallowing and in response to noxious chemical irritation of the airway (e.g., smoke or water in the nasal passages).38

Superimposed upon these metabolic demandsand basic reflexes,theforebraincancommand a wide range of respiratory responses. Respiration can be altered by emotional response, and it increases in anticipation of metabolic 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 cortex, which provides premotor and motor integration 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 lowered by a brief period of hyperventilation, a healthy awake subject will nevertheless continue to breathe with a normal rhythm, at least initially,39 albeit at reduced volume, until the PCO2 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 posthyperventilation apnea.40 Their respirations stop after deep breathing has lowered the carbon 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 differential diagnosis of lethargic or confused patients, 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 patient’s chest, to make it easier later to detect when breathing has restarted, and to count the breaths. If the lungs function well, the maneuver usually lowers the arterial carbon dioxide by 8 to 14 torr. At the end of the deep breathing, wakeful patients without brain damage show little or no apnea (less than 10 seconds). However, in patients with forebrain impairment, the period of apnea may last from 12 to 30 seconds. The neural substrate that produces a continuous breathing pattern even in the absence of metabolic need is believed to include the same frontal pathways that regulate behavioral alterations of breathing patterns, as the continuous breathing pattern disappears with sleep, bilateral frontal lobe damage, or diffuse metabolic impairment of the hemispheres.

CHEYNE-STOKES RESPIRATION

Cheyne-Stokes respiration41 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 hyperpneic 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,

is reached. The hyperpneic phase usually lasts longer than the apneic phase (Figure 2–5).

This rhythmic alternation in Cheyne-Stokes respiration results from the interplay of normal brainstem respiratory reflexes.42–45 When the medullary chemosensory circuits sense adequate oxygen and carbon dioxide tension, they reduce the rate and depth of respiration, causing a gradual rise in arterial carbon dioxide tension. There is normally a short delay of a few seconds, representing the transit time for fresh blood from the lungs to reach the left heart and then the chemoreceptors in the carotid

artery and the brain. By the time the brain begins increasing the rate and depth of respiration, the alveolar carbon dioxide has reached even higher levels, and so there is a gradual ramping up of respiration as the brain sees a rising level of carbon dioxide, despite its additional efforts. By the time the brain begins to see a fall in carbon dioxide tension, the levels in the alveoli may be quite low. When blood containing this low level of carbon dioxide reaches the brain, respiration slows or may even cease, thus setting off another cycle. Hence, the periodic cycling is due to the delay (hys-

teresis) in the feedback loop between alveolar ventilation and brain chemoreceptor sensory responses.

The Cheyne-Stokes respiratory cycle is not usually seen in normal individuals because the circulatory delay between a change in alveolar blood gases and carbon dioxide tension in the brain is only a few seconds. Even as circulatory delay rises with cardiovascular or pulmonary disease, during waking the descending pathways that prevent posthyperventilation apnea also ensure the persistence of respiration even during periods of low metabolic need, thus damping the oscillations that produce CheyneStokes respiration. However, during sleep or with bilateral forebrain impairment, due either to a diffuse metabolic process such as uremia, hepatic failure, or bilateral damage such as cerebral infarcts or a forebrain mass lesion with diencephalic displacement, periodic breathing may emerge.43–45 In patients with heart failure, the transit time for blood from the lungs to reach the carotid and cerebral chemoreceptors can become so prolonged as to produce a Cheyne-Stokes pattern of respiration, even in the absence of forebrain impairment. Thus, Cheyne-Stokes respiration is mainly useful as a sign of intact brainstem respiratory reflexes in the patients with forebrain impairment, but cannot be interpreted in the presence of significant congestive heart failure.

HYPERVENTILATION IN

COMATOSE PATIENTS

Sustained hyperventilation is often seen in patients with impaired consciousness, but is usually a result of either hepatic coma or sepsis, conditions in which circulating chemical stimuli cause hyperpnea, or a metabolic acidosis, such as diabetic ketoacidosis (see Chapter 5). Other patients have meningitis caused either by infection or subarachnoid hemorrhage, which stimulates chemoreceptors in the brainstem,46 probably by altering CSF pH.

Some patients hyperventilate when intrinsic brainstem injury or subarachnoid hemorrhage or seizures cause neurogenic pulmonary edema.47 The ventilatory response is driven by pulmonary mechanosensory and chemosensory receptors. The pulmonary congestion lowers both the arterial carbon dioxide and the oxygen tension. Stimulation of pulmonary stretch re-

ceptors is apparently sufficient to cause reflex hyperpnea, as oxygen therapy sufficient to raise the arterial oxygen level does not always correct the overbreathing.

Another small group of patients has been identified who have hyperventilation associated with brainstem gliomas or lymphomas.48,49 These patients have spinal fluid that is acellular, but generally acidotic compared to arterial pH. In others, the lumbar CSF may have a normal pH, but it is believed that the tumor causes local lactic acidosis, which may trigger brain chemoreceptors to cause hyperventilation (Figure 2–5).

It is theoretically possible for an irritative lesion in the region of the parabrachial nucleus or other respiratory centers to produce hyperpnea.37 The diagnosis of such true ‘‘central neurogenic hyperventilation’’ requires that with the subject breathing room air, the blood gases show elevated arterial oxygen tension, decreased carbon dioxide tension, and an elevated pH. The cerebrospinal fluid likewise must show an elevated pH and be acellular. The respiratory changes must persist during sleep to eliminate psychogenic hyperventilation, and one must exclude the presence of stimulating drugs, such as salicylates, or disorders that stimulate respiration, such as hepatic failure or underlying systemic infection. Cases fulfilling all of these criteria have rarely been observed,50,51 and none that we are aware of has come to postmortem examination of the brain.

APNEUSTIC BREATHING

Apneusis is a respiratory pause at full inspiration. Fully developed apneustic breathing, with each cycle including an inspiratory pause, is rare in humans, but of considerable localizing value. Experiments in animals indicate that apneusis develops with injury to the pontine respiratory nuclei described above, and experi-

ence with rare human cases would support this view52,53 (see Figure 2–5).

Clinically, end-inspiratory pauses of 2 to 3 seconds usually alternate with end-expiratory pauses, and both are most frequently encountered in the setting of pontine infarction due to basilar artery occlusion. However, apneustic breathing may rarely be observed in metabolic encephalopathies, including hypoglycemia, anoxia, or meningitis. It is sometimes observed