Contraction of airway smooth muscle is believed to be the most important factor producing acute airway obstruction. For many years, an enhancement of airway smooth muscle responsiveness to contractile agonists was assumed to be a major mechanism of asthma; however, in vitro and in vivo studies have not consistently demonstrated this pathophysiology. Instead of an enhancement in responsiveness to contractile stimuli, a reduction in responsiveness to relaxant stimuli may contribute to airway obstruction. Although the mechanism for this effect is poorly understood, a reduction in airway sensitivity to beta-adrenergic agonists could contribute to airway hyperresponsiveness by altering the balance between constricting and dilating influences.

A balance between constricting and dilating influences also exists with respect to the autonomic nervous system. A shift in this balance, with an increase in constricting influences, may be a mechanism of asthma.

The parasympathetic nervous system provides the dominant constrictor input to the airways ( Fig. 51.1 ). Efferent cholinergic fibers travel in the vagus nerve to synapse in ganglia within the airway wall. Postganglionic fibers release acetylcholine to activate muscarinic receptors and stimulate airway smooth muscle contraction. A negative feedback system limits release of acetylcholine from nerve terminals. Muscarinic autoreceptors, or receptors on the nerve ending, also are activated by acetylcholine and inhibit further release of acetylcholine from the nerve terminal.

Neural Control of the Airway. Parasympathetic, sympathetic, and nonadrenergic noncholinergic (NANC) efferents innervate ganglia within the airway wall. Postganglionic cholinergic efferents release acetylcholine (ACh) to constrict airway smooth muscle. Postganglionic NANC efferents release nitric oxide (NO) to relax airway smooth muscle. Circulating epinephrine relaxes the airway. Afferents from the airway originate in the epithelium and are activated by airway irritation, as occurs with tracheal intubation.

The importance of exaggerated cholinergic efferent activity in the pathogenesis of airway hyperreactivity has been debated extensively. The relatively limited efficacy of anticholinergic agents in relieving clinical bronchospasm and growing evidence supporting other mechanisms suggest that this pathway has a limited role in the pathophysiology of asthma. However, this mechanism appears to be very important in the perioperative management of asthmatic subjects. Reflex stimulation of airway smooth muscle during placement of a tracheal tube represents one of the most important causes of bronchospasm in the perioperative period.

An alternative mechanism by which the parasympathetic nervous system may contribute to airway hyperresponsiveness is through dysfunction of the muscarinic autoreceptors, which allows increased postganglionic release of acetylcholine after reflex stimulation. This mechanism may explain the airway hyperresponsiveness that occurs for several weeks after an upper respiratory tract infection, although additional autoreceptor-independent mechanisms may also be present. The role of this mechanism in the pathophysiology of clinical asthma is unclear.

The sympathetic nervous system primarily acts to decrease airway tone. In contrast to the parasympathetic nervous system, sympathetic innervation of airway smooth muscle in humans is either sparse or absent. Circulating catecholamines activate beta-adrenergic receptors in airway smooth muscle and provide the primary sympathetic input to human airways. Because airways of normal human subjects do not become hyperresponsive after beta-adrenergic blockade, it is unlikely that impaired catecholamine secretion contributes significantly to the pathogenesis of asthma.

The alpha-adrenergic system is thought to play a relatively minor role in determining the state of airway responsiveness. Although alpha-adrenergic receptors are present in human airways, the protective effects of alpha-adrenergic antagonists have been disappointing and can be attributed to other properties, such as antihistamine activity.

In addition to cholinergic and adrenergic input, a third neural system, the nonadrenergic noncholinergic (NANC) system, provides efferent nerves to the airways. Both constricting and dilating pathways have been identified. Nitric oxide serves as the inhibitory NANC neurotransmitter in human airways. A relative increase in constricting influences or a decrease in dilating influences in the NANC system could potentially contribute to asthma. However, asthmatic subjects demonstrated no deficit in NANC inhibitory pathways, and inhibition of NANC excitatory neurotransmission did not improve airway hyperresponsiveness. Thus, current evidence does not support imbalance of the NANC system as a major mechanism of asthma.

Airway inflammation appears to serve primarily as a modulating influence in asthma. Inflammation is certainly present in some but not all asthmatic subjects. The process of inflammation involves airway wall edema and infiltration of the mucosa by a variety of inflammatory cells, including neutrophils, mast cells, helper T lymphocytes, macrophages, and eosinophils. These cells produce and release mediators of inflammation, such as histamine, leukotrienes, platelet-activating factor, prostaglandins, thromboxanes, cytokines, serotonin, and nitric oxide. Airway inflammation can also reduce airway diameter. Airway hyperresponsiveness is correlated with increased baseline airway tone. Although inflammation appears to modulate the course of asthma, other factors certainly contribute to the pathogenesis.

The epithelium provides a barrier to protect the subepithelial layers against stimuli that could provoke bronchospasm. Airways of asthmatic subjects demonstrate areas of epithelial destruction, and the clinical significance of this finding has been demonstrated.

The epithelium not only serves as a barrier but also plays an active role in the maintenance of airway tone, producing constricting and dilating factors. An alteration in the balance between these factors could alter airway responsiveness. The relative importance of alterations in epithelial function in the pathogenesis of asthma is unknown.

The classic symptoms of asthma include wheezing, cough, dyspnea, and chest tightness. A patient’s medical history also should include information about the pattern and severity of the symptoms, precipitating and aggravating factors, and the duration and course of these symptoms.

Physical examination is directed to the respiratory tract. Auscultation of the chest may reveal expiratory wheezing and a prolonged phase of expiration. During asthma exacerbations, wheezes may not be heard because of severely reduced air exchange. The airway examination may also be notable for allergic rhinitis or nasal polyps, which are associated with asthma.

Laboratory studies that aid in the diagnosis of asthma depend on findings from the medical history and physical examination. In general, pulmonary function tests are useful to document the severity and establish the reversibility of obstruction; spirometry tests used in patients with asthma are shown in Box 51.1 . Although these tests may aid the diagnosis of asthma, pulmonary function measurements often do not correlate directly with symptoms. An expert working group of the National Heart, Lung and Blood Institute recommended that spirometry measurements before and after inhalation of a short-acting bronchodilator should be undertaken for patients in whom the diagnosis of asthma is being considered.

For patients in whom the diagnosis is uncertain using traditional methods, the National Asthma Education and Prevention Program (NAEPP) conditionally recommends measurement of fractional exhaled nitric oxide (FeNO) to aid the diagnosis.

The overall course of asthma has been reported to improve, worsen, or remain the same during pregnancy. A likely reason for the variation in the results of published studies is a difference in methods of assessing the severity of asthma. Most studies have used either clinical symptoms or requirements for pharmacologic therapy as indicators of the course of the disease. These measures do not correlate with objective measures of airway obstruction. A US obstetric cohort study found that exacerbations of asthma during pregnancy occur in as many as 40% of subjects receiving standard clinical care, and risk of exacerbation correlates with severity of prepregnancy asthma.

Several mechanisms may be responsible for the changes in the clinical course of asthma during pregnancy ( Box 51.2 ). An increase in progesterone level is thought to be one mechanism that improves asthma during pregnancy. Progesterone relaxes uterine and gastrointestinal smooth muscle and may or may not have similar effects on airway smooth muscle. Conversely, progesterone may actually worsen asthma by enhancing inflammation. Thus, effects of pregnancy on asthma appear to involve a number of factors other than direct effects of hormones on airway smooth muscle.

Many investigators have questioned whether maternal asthma adversely affects perinatal outcome. Variation in study design (e.g., retrospective and prospective) and differences in severity and treatment of asthma may account for differences in study results. A systematic review reported increased incidences of cesarean delivery, gestational diabetes, antepartum and postpartum hemorrhage, placenta previa and abruption, and premature rupture of membranes in patients with severe asthma. Moderate to severe asthma increased the risk for cesarean delivery and gestational diabetes compared with mild asthma. Although asthma in pregnancy is associated with an increased risk for adverse perinatal outcomes, a metaanalysis of cohort studies suggested that active asthma management, which is intended to reduce the exacerbation rate, may reduce the risk for perinatal complications, particularly preterm delivery. No controlled studies have documented better perinatal outcome with aggressive asthma treatment. Potential mechanisms of increased perinatal morbidity and mortality in patients with uncontrolled asthma include hypoxemia and hypocapnia, inflammation, and altered placental function from asthma-associated mediator release. A prospective cohort study of nearly 80,000 parous women demonstrated that hypertensive disorders of pregnancy were associated with an increased risk for asthma, which may reflect shared mechanisms such as vascular remodeling and endothelial abnormalities.

Beta-adrenergic agonists exert beneficial effects in asthmatic patients by activation of beta ₂ -adrenergic receptors, which mediate several processes ( Box 51.3 ). Short-acting beta-adrenergic agonists (SABAs) are frequently used for acute exacerbations of asthma. Long-acting beta-adrenergic agonists (LABAs) , when combined with inhaled corticosteroids (ICSs), are also effective in treating acute asthma and for asthma maintenance. Both SABAs and LABAs may be administered as aerosols, orally, or parenterally. The aerosol route is generally preferred during pregnancy because high concentrations of the medication can be delivered directly to the site of action in the airways, with relatively less drug delivered to the uteroplacental circulation.

The limited number of human studies investigating the fetal safety of long-term administration of beta-adrenergic agonists have not shown significant adverse neonatal outcomes. In addition, the long history of use of these agents without reports of teratogenicity suggests that their use should not be restricted because of fetal concerns (see Chapter 16 ).

Methylxanthines (e.g., theophylline , aminophylline ) were used for many years in the long-term treatment of asthma. Although their mechanism of action is controversial, relaxation of airway smooth muscle is the most prominent effect. The ability of these agents to inhibit intracellular phosphodiesterase and increase concentrations of cyclic adenosine monophosphate (cAMP) is not the mechanism of bronchodilation, because these effects do not occur at clinically relevant concentrations in vivo . Their use is now limited to patients whose asthma responds poorly to other forms of therapy. Methylxanthines do not appear to cause significant adverse fetal outcomes. Serum concentrations of theophylline should be monitored carefully, especially in the third trimester, when theophylline clearance decreases.

Bronchodilation with anticholinergic agents occurs through the blockade of muscarinic receptors on airway smooth muscle. Because of their limited efficacy, the NAEPP recommends only using anticholinergic medications in combination with other bronchodilators or antiinflammatory agents. The quaternary anticholinergic agent ipratropium bromide can be delivered as an aerosol, allowing higher concentrations in the lung with reductions in systemic absorption and potential effects on the fetus. Human data on the safety of anticholinergic agents and on potential teratogenicity are lacking, but ipratropium bromide is not associated with teratogenicity in animal studies.

Magnesium sulfate relaxes airway smooth muscle, most likely via its antagonism of calcium entry into airway smooth muscle cells. Its use is limited primarily to acute bronchospasm.

Proposed mechanisms of action for corticosteroids are (1) decreases in cellular infiltration and mediator release, (2) reduction in airway permeability, and (3) upregulation of the beta-adrenergic system. Unlike bronchodilators, corticosteroids not only reduce airway sensitivity to a constrictor stimulus but also decrease the maximal extent of airway narrowing, a feature that may predict severity of an acute asthmatic episode.

Both systemic and inhaled corticosteroids serve as mainstays in acute and maintenance asthma therapy. Neither systemic nor inhaled corticosteroids have been proven to increase the risk for congenital malformations in humans, but ICSs are preferred over systemic corticosteroids because of fewer maternal side effects and reduced delivery to the fetus. Systemic corticosteroids are now limited to acute exacerbations and persistent, severe asthma. Although oral corticosteroid use is associated with an increased incidence of low-birth-weight infants, ICSs do not appear to increase perinatal risk.

Corticosteroids may exacerbate maternal glucose intolerance, especially in women who also receive treatment with a beta-adrenergic agonist. Thus, careful monitoring of maternal glucose concentration is indicated when corticosteroids are used. However, because corticosteroids are efficacious in controlling severe asthma during pregnancy, these agents should not be withheld from the medical regimen.

Some authorities have recommended that corticosteroid-dependent asthmatic women receive large doses of parenteral corticosteroids during labor to prevent complications related to adrenal suppression. The scientific basis for this recommendation is questionable as ICSs in moderate doses do not produce adrenocortical suppression. The potential for adrenal insufficiency in infants of asthmatic mothers taking systemic or inhaled corticosteroids appears to be very low, most likely owing to the widespread use of either prednisone or prednisolone. In the mother, prednisone is converted rapidly to prednisolone, which crosses the placental barrier to a very limited extent.

Cromolyn sodium and nedocromil sodium belong to a class of drugs that are thought to reduce inflammation and mediator release primarily by stabilizing mast cells and perhaps other inflammatory cells. These medications are no longer recommended for asthma management.

Based on the observation that leukotrienes are released into the airways by immune cells and contribute to the inflammatory process, other forms of antiinflammatory therapy are leukotriene receptor antagonists and leukotriene synthesis inhibitors . Safety data for the use of these agents in pregnancy are scarce (see Chapter 16 ). A large, retrospective cohort analysis that included more than 1500 women who received montelukast during pregnancy found no difference in congenital malformations compared with women who did not have asthma.

A recombinant monoclonal anti-IgE antibody, omalizumab , is used specifically in patients with allergic asthma that is refractory to ICSs. A prospective, observational study of 250 women who received omalizumab during pregnancy demonstrated no increased risk of major congenital malformations, preterm birth, and small-for-gestational-age babies compared with pregnant women with asthma who did not receive the medication. Omalizumab may be continued in women who are already receiving therapy and become pregnant if the benefit is deemed to outweigh potential harm.

During the preoperative evaluation, the anesthesia provider should assess the severity of the disease and whether an acute asthmatic episode is present. The medical history should include information about symptoms of wheezing, dyspnea, and cough. Further information should be sought about the frequency and severity of symptoms, the course of these symptoms during pregnancy, and the date of the most recent exacerbation, as well as any history of tracheal intubation or hospitalization. Patients who have frequent, severe attacks are at increased risk for morbidity in the peripartum period.

Physical examination should focus on the pulmonary system. Chest auscultation may demonstrate wheezing with or without a prolonged expiratory phase. However, wheezing may not be audible if air movement is markedly reduced. Additional signs of an acute exacerbation of asthma include tachypnea, exaggerated (>20 mm Hg) pulsus paradoxus, and the use of accessory respiratory muscles.

In a pregnant woman with stable asthma, laboratory tests add little to anesthetic management. However, if an acute exacerbation is suspected, chest radiographic examination, arterial blood gas measurement, and pulmonary function tests may assist with diagnosis and therapy. Chest radiographic examination helps diagnose precipitating or complicating conditions such as pneumonia, pneumothorax, and heart failure. During an episode of acute asthma, arterial blood gas measurement often shows hypoxemia and respiratory alkalosis. After a prolonged, severe episode, arterial carbon dioxide tension increases as a result of fatigue. Spirometry measures the volume of gas exhaled over time (see Box 51.1 ). The most convenient indirect measurement for assessing airway obstruction during labor is the peak expiratory flow rate , which can be measured at the bedside with a flowmeter.

The goals of analgesia for labor and delivery in asthmatic women include (1) provision of pain relief, (2) reduction in the stimulus to hyperpnea, and (3) prevention or relief of maternal stress. The goal of adequate pain relief does not differ for asthmatic women. It is important to prevent hyperpnea and stress in women with a history of asthmatic episodes triggered by exercise or stress. These goals should be accomplished with minimal sedation, minimal paralysis of the muscles of respiration, and minimal depression of the fetus, and can be accomplished with a number of analgesic modalities.

Systemic opioids may provide reasonable pain relief and reduce the stimulus to hyperpnea, especially during the early part of the first stage of labor. In theory, opioids reduce the risk for bronchospasm in asthmatic subjects. Opioid receptors are believed to be present in the respiratory tract and to inhibit release of excitatory neuropeptides. The clinical relevance of these findings is unknown, because moderate doses of inhaled morphine do not significantly alter airway tone. Conversely, high doses of some opioids (e.g., morphine) may increase the risk for bronchospasm by releasing histamine. The risk associated with using moderate doses of morphine does not seem excessive, because airway tone does not change in subjects with moderate to severe asthma after inhalation of morphine. An opioid that does not release histamine (e.g., fentanyl , remifentanil ) may be a better choice for the asthmatic parturient. High doses of opioids are not desirable in subjects with active wheezing because of the risks for maternal and neonatal respiratory depression (see Chapter 23 ).

Neuraxial analgesic techniques, including epidural or combined spinal-epidural (CSE) analgesia, provide continuous pain relief with a reduction in the stimulus to hyperventilation (see C hapter 24 ). These goals typically are achieved without maternal sedation or neonatal depression. Unlike other analgesic techniques, continuous lumbar epidural analgesia adds a margin of safety by providing the opportunity to extend the sensory block for cesarean delivery. The possibility of extension allows the anesthesia provider to avoid some of the risks associated with general anesthesia, particularly airway manipulation and bronchospasm. The most significant disadvantage of epidural anesthesia in an asthmatic subject is the risk of high thoracic motor block and respiratory insufficiency. Use of an appropriate epidural test dose and maintenance of sensory level at the T10 dermatome minimize this risk. In addition, the use of a dilute concentration of local anesthetic combined with a modest dose of a lipophilic opioid produces satisfactory analgesia with less motor block than local anesthetic alone.

The choice between neuraxial anesthesia and general anesthesia for cesarean delivery depends on obstetric considerations and the respiratory status of the parturient. In general, avoidance of airway instrumentation is desirable because tracheal intubation markedly increases airway tone in asthmatic subjects.

The most important advantage of neuraxial anesthesia in the asthmatic patient is the avoidance of tracheal intubation. Stable asthmatic patients can undergo either spinal or epidural anesthesia. In unstable asthmatic patients who require the use of accessory muscles of respiration, neuraxial anesthesia may be hazardous because of impaired ventilatory capacity in the presence of a high thoracic motor block. Although it has been suggested that ropivacaine and levobupivacaine may cause less motor block than bupivacaine, decreases in maternal pulmonary function tests were similar following spinal anesthesia with bupivacaine, ropivacaine, or levobupivacaine for cesarean delivery.

The adrenal medulla receives innervation from preganglionic sympathetic fibers arising from the T6 to L2 spinal segments. Some authors have postulated that neuraxial anesthesia and the ensuing sympathectomy could precipitate or potentiate bronchospasm during cesarean delivery in asthmatic subjects by reducing adrenal output of epinephrine (adrenaline). This possibility seems remote. First, although epinephrine infusion can reduce airway reactivity in asthmatic subjects, epinephrine concentrations do not decrease during nonobstetric surgery performed with neuraxial anesthesia that achieves high thoracic sensory levels. Second, the contention that neuraxial anesthesia may prevent increases in circulating epinephrine that are required to compensate for stress-induced bronchospasm does not appear to be valid. Bronchoconstriction does not stimulate epinephrine secretion in human asthmatic subjects. Thus, neuraxial anesthesia is appropriate for cesarean delivery in stable asthmatic subjects.

General anesthesia for asthmatic women undergoing cesarean delivery requires a balance between the competing considerations of pulmonary aspiration and intraoperative bronchospasm. Although airway instrumentation provides a significant stimulus for bronchospasm, the high risk for aspiration mandates tracheal intubation during administration of general anesthesia in parturients.

The main options for tracheal intubation are rapid-sequence induction and awake fiberoptic intubation, although inhalational induction of general anesthesia with sevoflurane has been described in a parturient with status asthmaticus. Indications for awake intubation in asthmatic subjects are similar to those for nonasthmatic patients. Pretreatment with a local anesthetic and a beta-adrenergic agonist can attenuate reflex-induced bronchoconstriction. The benefits of topical local anesthesia and airway nerve blocks for awake intubation should be weighed against a possible increase in the risk for aspiration from the loss of protective airway reflexes. Rapid-sequence induction for cesarean delivery in asthmatic patients is most often accomplished using either propofol or ketamine , with ketamine long considered the agent of choice because of its sympathomimetic properties, which relax airway smooth muscle and inhibit neural reflexes. Beneficial airway effects of propofol also appear to occur via inhibition of airway reflexes. Intravenous lidocaine (lignocaine) , administered prior to the induction agent, inhibits airway reflexes and attenuates irritant-induced bronchoconstriction, including during tracheal intubation, and produces an additional protective effect above that of beta-adrenergic agonist pretreatment alone.

Although volatile halogenated anesthetic agents can relax uterine tone, their use should be considered for the maintenance of anesthesia. These agents attenuate airway responsiveness through direct effects on airway smooth muscle, inhibition of airway reflexes, and effects on the epithelium. If possible, the inhaled concentration should be administered at less than 0.5 minimum alveolar concentration to limit the possibility of uterine relaxation and hemorrhage. Sevoflurane acts as a bronchodilator in large and small airways and reverses airway constriction associated with tracheal intubation. Desflurane may have irritant effects on the airway owing to smooth muscle contraction in the airway. Based on a systematic review, isoflurane and sevoflurane are considered superior to desflurane in asthmatic patients.

An inhaled bronchodilator can be added if bronchospasm occurs. The potential disadvantage of this technique is that the most effective bronchodilators (i.e., the beta-adrenergic agonists) also relax uterine smooth muscle. The administration of a beta-adrenergic agonist by aerosol delivers a relatively greater dose of drug to the airways and minimizes uterine relaxation.

Emergence from general anesthesia, as with induction, requires a balance between reducing the risk for aspiration and lowering the risk for bronchospasm. Extubation of the trachea when the patient is awake minimizes the risk for aspiration, but the tracheal tube may stimulate reflexes and precipitate bronchospasm as the depth of anesthesia is reduced. If bronchospasm occurs during emergence, bronchodilators can be administered.

The following factors may contribute to the deterioration of pulmonary function during pregnancy: (1) increased airway responsiveness and obstruction (as can occur in patients with asthma), (2) increased work of breathing, and (3) cardiovascular changes such as congestive heart failure and pulmonary hypertension associated with the increased blood volume of pregnancy.

In spite of potential negative effects of pregnancy on the course of CF, long-term maternal outcome does not appear to be affected. However, temporary reductions in FEV ₁ in the immediate postpartum period may occur, and prepregnancy FEV ₁ is a useful predictor of ability to tolerate pregnancy.

CF has been associated with an increased risk for low-birth-weight infants and preterm delivery, but recent evidence suggests that improved care of these patients can mitigate these problems. Affected women with poor prepregnancy FEV ₁ (≤50% predicted) are more likely to have cesarean delivery, preterm delivery, and low-birth-weight infants compared with women with FEV ₁ > 50% predicted. Potential mechanisms for these complications include chronic hypoxemia and poor maternal nutrition. Pancreatic insufficiency, poor nutritional status, CF-related diabetes mellitus, poor cardiac function, and high bacterial burden have been associated with poorer pregnancy outcomes.