Respiratory Muscles

A number of muscles are important for respiration. The main inspiratory muscles include the diaphragm, external intercostal and scalene muscles, with accessory muscles being the sternocleidomastoid, pectoralis major and minor, serratus anterior, latissimus dorsi, and serratus posterior superior. The expiratory muscles are the internal intercostals, external oblique, internal oblique, rectus abdominis, transverse abdominis, and serratus posterior inferior. The muscles of the upper airway do not have a direct action on the chest cage but are required to keep the airway open during inspiration, regulate airway resistance, and partition airflow through nasal and oral pathways. These are the muscles of the soft palate, pharynx, larynx, trachea, nose, and mouth innervated by cranial nerves V, VII, IX, X, and XII.

Chemical Control of Breathing

Breathing is influenced by both peripheral and central chemoreceptors, and may be impaired by damage to these receptors or their neural connections. Peripheral chemoreceptors are located in the carotid and aortic bodies and are innervated by the glossopharyngeal nerve, which projects to the tractus solitarius. These receptors are primarily activated by hypoxia, and also by reduced arterial pH, increased arterial pCO ₂ , and hypoperfusion. Central chemoreceptors are located in the locus ceruleus and nuclei of the tractus solitarius, midline (raphe) of the ventral medulla, and ventrolateral quadrant of medulla. They respond primarily to high pCO ₂ mediated through the detection of a fall in the pH of the cerebrospinal fluid (CSF), and are crucial for adequate breathing in sleep. The sensation of breathlessness is probably mediated through these medullary chemoreceptors or respiratory neurons. In congenital hypoventilation syndrome, periods of cyanosis occur during sleep due to deficiency of central chemoreception, with reduced or absent CO ₂ sensitivity; mutations of the PHOX2B gene are sometimes responsible. These patients, in contrast to patients with locked-in syndrome, do not experience air hunger or breathlessness with hypercapnia.

Brainstem Respiratory Centers

There are three important brainstem respiratory centers: the pneumotaxic center or pontine respiratory group (PRG) in the dorsal lateral pons, and the dorsal (DRG) and ventral respiratory groups (VRG) in the medulla ( Fig. 1-2 ). The PRG contains inspiratory, expiratory, and phase-spanning neurons, receives vagal afferents relating to lung volume, and modulates respiratory frequency. Its primary connections are with medullary respiratory neurons, but it also has connections with the hypothalamus, cerebral cortex, and the nucleus of tractus solitarius. PRG neurons are not essential for respiratory rhythm generation, and transection at this level produces regular breathing; vagotomy then results in slowing of the respiratory rate but not in alteration of rhythm. The center is involved in modification and fine control of respiratory rhythm. Apneusis is defined as prominent end-inspiratory pauses that can be produced by pontine transections in vagotomized animals.

Representation of the brainstem respiratory centers and tracts. On the left side, the nuclei are shown in light purple and the adjacent respiratory groups are orange. On the right side, the dorsal respiratory group (DRG) is located within the solitary nucleus, and the ventral respiratory group (VRG) is ventral to the nucleus ambiguus. Bot, Botzinger complex.

(Adapted from Bolton CF, Chen R, Wijdicks EFM, et al: Neurology of Breathing. Butterworth Heinemann, Philadelphia, 2004, with permission.)

The medullary respiratory neurons generate the respiratory rhythm, and transection of the brainstem at the pontomedullary level allows rhythmic ventilator excursions to persist, whereas these movements are abolished by transection at the medullary-cervical region. The output from the medullary respiratory centers descends in the reticulospinal tract in the anterolateral funiculus of the spinal cord. DRG neurons are mainly inspiratory and are located in the ventrolateral portion of the nucleus of the tractus solitarius, primarily discharging during inspiration, and receiving pulmonary afferents via the vagus nerves. These neurons primarily project to the contralateral spinal motor neurons, and probably serve as the primary rhythmic drive to phrenic motor neurons. DRG neurons are modulated by GABA _B receptors.

The VRG neurons are both inspiratory and expiratory neurons, situated in a bilaterally symmetric column that extends from the caudal level of the facial nucleus to the rostral cervical spinal cord. The cell bodies are located within the nucleus ambiguus and nucleus retroambigualis and are responsible for the generation of respiratory rhythm. NMDA receptors are the major mediators of VRG ventilatory drive, with modulation by non-NMDA glutamate systems.

The cerebellum also influences breathing. In animals, stimulation of the fastigial nucleus produces early termination of bursting of both the inspiratory and expiratory neurons. Functional imaging studies in humans have also documented activation of cerebellum along with other brainstem and basal forebrain structures during volitional breathing.

Voluntary Control of Breathing

Voluntary control of breathing is mediated by the descending corticospinal tract and its influence on the motor neurons innervating the diaphragm and intercostal muscles. The rate and rhythm of breathing are influenced by the forebrain, as observed during voluntary hyperventilation or breath-holding as well as during the semivoluntary or involuntary rhythmic alterations in ventilatory pattern that are required during speech, singing, laughing, and crying.

Electrophysiologic and imaging studies support the belief that specific areas of cortex are involved in different phases of voluntary breathing. The diaphragm can be activated by stimulation of the contralateral motor cortex using transcranial magnetic stimulation. The diaphragm lacks significant bilateral cortical representation, consistent with the finding of attenuation of diaphragmatic excursion only on the hemiplegic side in patients with hemispheric stroke. The intercostal muscles are similarly affected by hemispheric lesions. Positron emission tomographic (PET) studies have shown an increase in cerebral blood flow in the primary motor cortex bilaterally, the right supplementary motor cortex, and the ventrolateral thalamus during inspiration; the same structures, along with the cerebellum, are involved in expiration.

The involvement of the forebrain in the regulation of breathing is further substantiated by the induction of apnea that follows stimulation of the anterior portion of the hippocampal gyrus, the ventral and medial surfaces of the temporal lobe, and the anterior portion of the insula. Ictal apnea has been reported during partial seizures in a patient with encephalitis who was found to have an abnormality of the left posterior lateral temporal region on single-photon emission computed tomography.

Integrated Neural Control of Breathing

The two types of control over breathing are highly integrated, as observed during speaking and singing, when automatic breathing is suppressed. Though the exact pathways of this coordination are not known, connections probably exist between the medullary respiratory centers, cerebral cortex, and extrapyramidal systems. In addition, integration occurs in the spinal cord between cortical, segmental, and breathing inputs to respiratory motor neurons.

Clinical Assessment

A detailed clinical history should be obtained including an account of any breathing or cardiac problems that presented prior to the onset of—or with a temporal relationship to—neurologic symptoms and of any antecedent illness (such as infection) that preceded onset of muscle weakness (e.g., in Guillain–Barré syndrome). The onset, distribution, character, and accompaniments of weakness may suggest the underlying cause. The history obtained from a bed-partner or caregiver is important in determining the presence of sleep-disordered breathing.

The respiratory and cardiac systems are examined to determine the respiratory rate and volume, pattern of breathing, heart rate, blood pressure, temperature, and presence of cyanosis. Bedside assessments should also include a single-breath counting exercise, observation of chest expansion, and testing of cough strength. Diaphragmatic weakness may give rise to paradoxic inward movement of the abdomen during inspiration. The presence of hypophonia, nasal intonation, dysarthria, dysphagia, and pooling of secretions suggest bulbar dysfunction. Auscultation of the chest may reveal features of bronchoconstriction, pulmonary congestion, or consolidation.

Tests of Respiratory Functions

Disorders of Involuntary Breathing

Disturbances of automatic breathing with intact volitional breathing lead to sleep apnea or Ondine curse; the patient can maintain respiration while awake (voluntarily), but experiences apnea or hypopnea during sleep. The underlying pathology involves the automatic ventilatory centers (VRG and DRG) and their descending connections. Typical clinical situations responsible include bilateral or unilateral medullary infarction, bulbar poliomyelitis, neurodegenerative disorders such as multiple system atrophy, syringobulbia, paraneoplastic brainstem syndromes, and idiopathic sleep apnea. Iatrogenic injury has been reported following bilateral cervical tractotomy performed for intractable pain, presumably as a result of damage to the descending reticulospinal tracts which activate phrenic motor neurons and the ascending spinoreticular fibers that carry afferent information to brainstem centers.

Disorders of Voluntary Breathing

The relatively pure form of voluntary breathing dysfunction is observed in the “locked-in” syndrome. Patients are unable to voluntarily control breathing and cannot speak, but they have a regular ventilatory pattern, preserved response to CO ₂ stimulation, and experience air hunger. Midpontine lesions are usually responsible due to infarctions (most often), hemorrhage, myelinosis, or tumor, resulting in disruption of the corticospinal and corticobulbar fibers that control voluntary respiration, while sparing the medullary respiratory centers that control automatic ventilation. Disordered voluntary breathing is also observed in extrapyramidal and cerebellar disorders, as discussed later.

Central Neurogenic Hyperventilation

Although central neurogenic hyperventilation was thought to be a classic and specific manifestation of midbrain dysfunction during transtentorial herniation, it is now apparent that this pattern of respiration is more common with unilateral or bilateral hemispheric lesions and carries a poor prognosis. This type of breathing can also occur with pontine or medullary lesions. The underlying mechanism of this tachypnea is unknown, and it may be the result of either stimulation of receptors in the pulmonary interstitial space secondary to congestion of neurogenic cause (neurogenic pulmonary edema), or central stimulation of medullary chemoreceptors secondary to local lactate production from tumor or stroke.

Other causes of centrally mediated hyperventilation are anxiety, infections, and drugs. The latter either stimulate the central or peripheral chemoreceptors or directly affect the brainstem respiratory neurons.

Apraxia of Breathing

Inability to take or hold a deep breath in spite of normal motor and sensory function of bulbar muscles is known as respiratory or breathing apraxia. This abnormality is most often found in elderly patients with cerebrovascular disease, dementia, or lesions of the nondominant hemisphere, and may be associated with frontal lobe release signs, paratonia, or other apraxias.

Posthyperventilation Apnea

In normal awake persons, there is a brief period of apnea after voluntary hyperventilation that is usually less than 12 seconds in duration when it follows five deep breaths sufficient to reduce pCO ₂ by 8 to 14 mmHg. It has been described in normal individuals engaged in an intellectual task. Apnea lasting more than 12 seconds was found in more than three-fourths of patients with bilateral CNS disease (structural or metabolic), compared to only 1 to 2 percent of normal subjects. It is equally common in patients with unilateral or bilateral brain injury, but is significantly more common in drowsy than alert patients (95 versus 48%). It is therefore likely that the degree of posthyperventilation apnea is an indicator of depressed CNS function.

Apneustic Breathing

Apneustic breathing is characterized by prominent, prolonged end-inspiratory pauses and is rare in humans. It has been reported following pontine section or vagotomy in animals and brainstem damage in humans.

Cheyne–Stokes Breathing

Cheyne–Stokes breathing is characterized by an escalating hyperventilation followed by decremental hyperventilation and finally apnea, which recurs in cycles. In humans, cycle lengths from 40 to 100 seconds may occur. During Cheyne–Stokes breathing, analysis of arterial blood gases shows an increasing pH and a declining pCO ₂ as a result of an increased respiratory drive and response to CO ₂ due to bilateral disease of the cerebral hemispheres. Cheyne–Stokes breathing was originally described in a patient who died of heart failure and is also a feature of cardiac dysfunction alone or in combination with CNS injury. It occurs with equal frequency in patients with supratentorial and infratentorial stroke, and it is also seen in premature infants during sleep and in subjects at high altitudes.

Ataxic Breathing

Ataxic or irregular breathing is usually due to medullary dysfunction and may be a terminal event in severe dysfunction of the lower brainstem. It is also seen in patients with autonomic failure from multiple system atrophy or familial dysautonomia.

Cluster Breathing

Cluster breathing is characterized by irregular groups of breaths interspersed with pauses of varying lengths. It can be seen in patients with lower medullary dysfunction or during sleep in patients with multiple system atrophy.

Other Conditions

In hiccup , there is strong contraction of the diaphragm and intercostal muscles followed by laryngeal closure, usually during inspiration. Hiccup rarely may be persistent and disabling. Persistent hiccup is associated with lateral medullary lesions, raised intracranial pressure, metabolic encephalopathy from diverse causes such as uremia, and any irritation of the diaphragm or phrenic nerves, but in many instances no cause can be found.

Sneezing and yawning are normal phenomena mediated through respiratory muscles. The center for sneezing is near the nucleus ambiguus, and yawning is coordinated from brainstem sites near the paraventricular nucleus via extrapyramidal pathways. A sneezing reflex triggered by sudden exposure to bright light may be inherited in an autosomal dominant manner. Yawning may initiate temporal lobe seizures, may be associated with arm stretching of the paretic limb in capsular infarction, or occur spontaneously in “locked-in” syndrome.

In diaphragmatic myoclonus or flutter (Leeuwenhoek disease), there is involuntary contraction of diaphragm during sleep or wakefulness at the rate of approximately 3 Hz. Diaphragmatic contractions cause epigastric pulsations and may be associated with dyspnea, hyperventilation, hiccups, belching, and difficulty in weaning from the ventilator. In the syndrome of isolated diaphragmatic tremor, there is usually no respiratory or functional disability and there is some voluntary control of the phenomenon ( Fig. 1-3 ).

Suppression of abnormal diaphragmatic tremor with voluntary wrist movements. The surface electromyographic (EMG) recordings from the left flexor carpi radialis (FCR) and needle EMG recordings from the right diaphragm in a 31-year-old man with isolated diaphragmatic tremor. There was rhythmic diaphragmatic EMG activity before, almost complete disappearance during, and resumption after a distracting task of left-hand metronome-guided finger tapping at 2 Hz.

(From Espay AJ, Fox SH, Marras C, et al: Isolated diaphragmatic tremor: is there a spectrum in “respiratory myoclonus”? Neurology 69:689, 2007, with permission.)

Central Nervous System

Strategic lesions in the brain or spinal cord can affect breathing and such neurologic disorders can be acute or chronic.

Acute Respiratory Dysfunction

Neurogenic Pulmonary Edema

Fluid movement from the pulmonary capillary bed into the alveolar air space is governed by the Starling equation, which expresses transcapillary fluid flux as a balance between intravascular pressure and plasma osmotic force. Dysfunction of the nervous system can result in increased pulmonary interstitial and alveolar fluid, leading to impaired alveolar gas exchange. This phenomenon, known as neurogenic pulmonary edema , may be life-threatening.

Neurogenic pulmonary edema has been reported in many conditions associated with severe brain injury such as head trauma, subarachnoid or intraparenchymal hemorrhage, ischemic stroke, multiple sclerosis, brain tumor, meningitis and encephalitis, status epilepticus, acute hydrocephalus, and spinal cord and meningeal hemorrhage. In a large series of 477 cases with subarachnoid hemorrhage, 8 percent had neurogenic pulmonary edema. Clinically, these patients had more severe bleeding than those without pulmonary edema, and 67 percent had increased intracranial pressure.

The exact mechanism involved is not known. Injury to the brain results in sympathetic discharges from the hypothalamus, brainstem, and spinal cord. Specific anatomic regions represent so-called trigger zones for neurogenic pulmonary edema, the most important of which are the A1 and A5 groups of neurons, nucleus of the solitary tract, the area postrema, the medial reticulated nucleus, and the dorsal motor nucleus of vagus. Flash pulmonary edema has been reported in a young woman with multiple sclerosis who had an acute demyelinating lesion at the rostromedial medulla ( Fig. 1-4 ). Stimulation of these specific regions (directly or indirectly) following brain injury can lead to sympathetic discharges, which cause severe systemic vasoconstriction and displace blood from the systemic to pulmonary circulation. Concomitantly, there is also reduced left ventricular diastolic and systolic compliance and increased left ventricular volume and left atrial filling pressure. These cardiac changes along with intensive pulmonary vasoconstriction lead to increased pulmonary capillary pressure with endothelial injury and leakage of fluid into the interstitial space and alveoli.

Magnetic resonance imaging (MRI) scans (transaxial and sagittal views) at 30 days before presentation (upper panel), 4 days after presentation (middle panel), and 60 days after presentation (lower panel) in a patient with neurogenic pulmonary edema. There is a hyperintense demyelinating lesion centered at the dorsomedial rostral medulla of the day 4 image on T2-weighted MRI, best appreciated on the axial view. No such lesion was visible 30 days before (upper panel) presentation. The perilesional edema had resolved at day 60 (lower panel).

(From Plummer C, Campagnaro R: Flash pulmonary edema in multiple sclerosis. J Emerg Med 44:e169, 2013, with permission.)

Increased capillary permeability may also contribute to the development of neurogenic pulmonary edema. This increased permeability is due to sympathetic microvascular stimulation causing micropores to increase in number and size, thereby allowing increased passage of fluid into alveoli as well as the release of several neurohumoral factors and inflammatory mediators such as neuropeptide Y, cytokines, fibrin and fibrin degradation products, plasma thromboplastin, and stress hormones such as corticotrophin releasing hormone, adrenocorticotrophic hormone, corticosteroids, and arginine vasopressin during CNS injury. Thromboplastin stimulates the process of extrinsic coagulation and may contribute to fibrin embolization of pulmonary vessels, resulting in increased capillary permeability.

Trauma to Brain and Spinal Cord

Head injury may cause respiratory compromise by direct trauma to the face, pharynx, larynx, and chest and through other effects such as diffuse axonal injury resulting in reduced central voluntary drive and neurogenic pulmonary edema. The practice of hyperventilation to reduce intracranial pressure possibly results in further ischemic insults to the brain.

Spinal cord injury can affect breathing in several ways ( Table 1-1 ), and the degree of respiratory dysfunction depends on the severity of injury, ranging from air hunger and loss of automated breathing in complete transverse cord injuries to regular rhythmic breathing with inability to take deep breaths, hold the breath, or cough on command in partial cord injuries. In patients with lesions above C3, apnea is usually permanent. With lesions below C3, especially in the mid- or lower cervical segments, some patients may still be weaned off the ventilator successfully. Delayed apnea in patients with cervical cord injury may arise secondary to manipulation of the spine in order to stabilize the fracture. In chronic injury, spasticity of the respiratory muscles may compromise vital capacity and inspiratory pressure. Dyspnea and wheezing in patients with spinal cord injury can also result from vagal overactivity due to sympathetic denervation.

Table 1-1

Mechanisms of Pulmonary Dysfunction in Patients with Spinal Cord Lesions

Injury to upper cervical cord leading to interruption of the descending respiratory control of the diaphragm and intercostal muscles

Direct injury to the anterior horn cells of the cervical and thoracic segments

Airway hyperactivity from loss of sympathetic airway innervation due to damage to sympathetic pathways in the spinal cord activating T1 to T6 ganglia

In advanced stages, spasticity of the respiratory muscles causing reduction in vital capacity and inspiratory pressure

 

Acute Nontraumatic High Myelopathies

Nontraumatic acute myelopathies include ischemic infarction of the spinal cord, hematomyelia, and postinfectious or immune-mediated myelopathies. The site and extent of the lesion affects respiration in a fashion similar to that described for traumatic injuries.

Multiple Sclerosis

Respiratory failure in advanced multiple sclerosis is often the cause of death. Single or multiple lesions in the cervical cord and lower brainstem cause respiratory dysfunction. Lesions of both corticospinal tracts or of the brainstem or upper cervical spinal cord cause paralysis of voluntary respiration, whereas those involving the dorsomedial medulla, nucleus ambiguus, and medial lemnisci result in loss of automatic respiration. Obstructive sleep apnea (OSA) may follow lesions in the medulla, and neurogenic pulmonary edema may occur with lesions in the region of nucleus tractus solitarius and the floor of the fourth ventricle.

Stroke

Respiratory compromise in stroke may be due to infarction or hemorrhage involving anatomic structures regulating breathing or as a consequence of secondary brain edema. Hemorrhagic strokes are more likely to produce early respiratory failure than ischemic strokes. Apnea, hypopnea, ataxic (irregular), tachypneic (central hyperventilation) and periodic (Cheyne–Stokes) breathing patterns have all been reported depending on the site of lesion. Although central neurogenic hyperventilation occurs with midbrain dysfunction from transtentorial herniation, it is also common with unilateral or bilateral hemispheric lesions. Ataxic breathing is more characteristic of medullary lesions and often seen terminally in patients with large stroke. Breathing abnormalities are common in pontine lesions as well as in secondary brainstem compression from expanding cerebellar hematomas. Infarction of the bilateral ventral pons results in the “locked-in” syndrome, where voluntary breathing is paralyzed (and the patient is unable to speak) due to interruption of the corticospinal and corticobulbar pathways; a normally functioning pontine tegmentum, cerebral hemispheres, and medulla results in preserved consciousness and regular automatic ventilation. In contrast, in sleep apnea (Ondine curse), automatic breathing is disturbed with preserved voluntary breathing in patients with bilateral or unilateral medullary infarctions. In focal hemispheric stroke, there may be contralateral dysfunction of chest wall movements.

Apart from anatomic lesions causing respiratory dysfunction, secondary factors following stroke increase the incidence of respiratory failure, such as oropharyngeal hypotonia due to reduced consciousness, impaired swallowing, and aspiration pneumonia.

The need for mechanical ventilation in patients with either brainstem or cerebral hemispheric stroke usually indicates a severe lesion. However, for patients requiring prolonged ventilation and tracheostomy, the likelihood of functional recovery is better in those with brainstem or cerebellar stroke than in those with hemispheric stroke.

Brain Tumors

Brainstem tumors such as gliomas, ependymomas, medulloblastomas, and cerebellar astrocytomas are more likely to cause respiratory disturbances than tumors in the cerebral hemispheres, often presenting acutely. Postoperative ventilatory support is often required. Supratentorial gliomas and other masses may also affect respiration due to tentorial herniation.

Peripheral Nervous System

Disorders of the peripheral nervous system ( Table 1-2 ) produce alveolar hypoventilation (pCO ₂ >50 mmHg), hypoxia, and finally apnea in advanced stages. Initially, patients with chronic neuromuscular disorders may not experience dyspnea, as there is decreased exercise demand due to the disease process. Mild respiratory dysfunction may present with signs of anxiety, sweating, tachycardia, and tachypnea, accompanied by a reduced single-breath count, decreased chest expansion, paradoxical inward movement of the abdomen during inspiration (suggesting diaphragmatic weakness), interrupted speech, and poor cough.

Table 1-2

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