Short-acting β₂ agonists bind to the β₂-adrenergic receptor located on the plasma membrane of smooth muscle cells, epithelial, endothelial, and many other types of airway cells.¹¹ This causes a stimulatory G protein to activate adenylate cyclase converting adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). It is unknown precisely how cAMP causes smooth muscle relaxation; however, decreases in calcium release and alterations in membrane potential are the most likely mechanisms. Longer acting β₂ agonists have the same mechanism of action as short-acting β₂ agonists; however, they have unique properties that allow for a longer duration of action. For example, salmeterol has a longer duration of action because a side chain binds to the β₂-receptor and prolongs the activation of the receptor.¹² The lipophilic side chain of formoterol allows for interaction with the lipid bilayer of the plasma membrane and a slow, steady release prolonging its duration of action.

β₂ agonists have a central role in the management of obstructive airway diseases allowing for control of symptoms and improvement in lung function. Short-acting β₂ agonists such as albuterol, levalbuterol, metaproterenol, and pirbuterol are prescribed for the rapid relief of wheezing, bronchospasm, and airflow obstruction. Clinical effect is seen in a matter of minutes and lasts up to 4 to 6 hours. Scheduled, daily use of short-acting β₂ agonists has largely fallen out of favor and they are now used primarily as rescue therapy.^13–15 Long-acting β₂ agonists are prescribed for control of symptoms when rescue therapies (i.e., short-acting β₂ agonists) are used greater than two times per week.¹⁶ Combination therapy including a long-acting β₂ agonist and an inhaled corticosteroid are effective in reducing symptoms, reducing the risk of exacerbation, and improving lung function while minimizing the dose of inhaled corticosteroid.¹⁷

Systemic absorption of inhaled β₂ agonists is responsible for a myriad of side effects, most of which are not serious. Most commonly, β₂ agonist therapy leads to tremors and tachycardia secondary to direct stimulation of the β₂-adrenergic receptor in skeletal muscle or vasculature, respectively.^18,19 In severe asthma, β₂ agonists may cause a temporary reduction in arterial oxygen tension of 5 mm Hg or more, secondary to β₂-mediated vasodilation in poorly ventilated lung regions.²⁰ Hyperglycemia, hypokalemia, and hypomagnesemia also can occur with β₂ agonist therapy but the severity of these side effects tends to diminish with regular use. Tolerance to β₂ agonists can occur with regular use over a period of weeks and, while not affecting peak bronchodilation, can be evidenced by a decrease in the duration of bronchodilation and the magnitude of side effects (tremor, tachycardia, etc.).^21,22 Tolerance likely reflects β₂-adrenergic receptor downregulation. β₂ agonist therapy withdrawal after regular use can produce transient bronchial hyperresponsiveness.

Evidence has associated the use of long-acting β₂ agonist therapy without concomitant use of a steroid inhaler with fatal and near-fatal asthma attacks.²³ In light of this evidence, it seems prudent to reserve long-acting β₂ agonists for patients that are poorly controlled on inhaled steroids alone or for those patients with symptoms sufficiently challenging to warrant the potential extra risk associated with use of the agents.

Systemic Adrenergic Agonists

Systemic administration of adrenergic agonists for asthma was used more frequently in the past. Oral, intravenous (IV), or subcutaneous administration of β-specific or nonspecific adrenergic agonists is now reserved for rescue therapy. The mechanism of action of systemically administered adrenergic agonists is the same as it is for inhaled agents. Binding of the drug to the β₂-adrenergic receptor on smooth muscle cells in the airway is responsible for the bronchodilatory effects. Specifically, β₂-receptor stimulation induces a stimulatory G protein to convert ATP to cAMP and in turn reduces intracellular calcium release and alters membrane potential.

Terbutaline can be given orally, subcutaneously, or intravenously, albuterol (salbutamol) can be given intravenously, and epinephrine is usually given subcutaneously or intravenously. Regardless of the route of administration, all three will produce bronchodilation. Comparison of IV and inhaled formulations of terbutaline failed to demonstrate any difference in bronchodilation and, with the propensity for IV formulations to cause side effects, inhaled therapy should be considered the first-line treatment.^24,25 This principle not only applies to terbutaline but all β-adrenergic agonists that are available in IV and inhaled forms. If inhaled therapy is not readily available or if inhaled therapy is maximized and symptoms persist, then subcutaneous epinephrine or terbutaline can be administered with improvement in symptoms and spirometry values.²⁶ In summary, subcutaneous or IV β agonists should be reserved only for rescue therapy.

The side effect profile of systemic adrenergic agonists is similar to the side effect profile for inhalational adrenergic agonists. The most common side effects are tremor and tachycardia. Arterial oxygen tension can be transiently decreased and hyperglycemia, hypokalemia, and hypomagnesemia can also be present. Escalating oral, subcutaneous, or IV doses can be associated with a greater incidence of side effects for the same degree of bronchodilation compared to inhaled β-adrenergic agonists.

Inhaled Cholinergic Antagonists

The use of anticholinergics for maintenance therapy and treatment of acute exacerbations in obstructive airway diseases is common. The parasympathetic nervous system is primarily responsible for bronchomotor tone and inhaled anticholinergics act on muscarinic receptors in the airway to reduce tone. The use of inhaled anticholinergics (see Table 25-1) in COPD as maintenance and rescue therapy is considered standard treatment.²⁷ Anticholinergics are not used for maintenance therapy in asthma and are only recommended for use in acute exacerbations.²⁸ The targets of therapy for anticholinergics are the muscarinic receptors located in the airway. There are three subtypes of muscarinic receptors found in the human airway.²⁹ Muscarinic 2 (M2) receptors are present on postganglionic cells and are responsible for limiting production of acetylcholine and protect against bronchoconstriction. M2 is not the target of inhaled anticholinergics but is antagonized by them. Muscarinic 1 (M1) and muscarinic 3 (M3) receptors are responsible for bronchoconstriction and mucus production and are the targets of inhaled anticholinergic therapy. Acetylcholine binds to the M3 and M1 receptors and causes smooth muscle contraction via increases in cyclic guanosine monophosphate (cGMP) or by activation of a G protein (Gq).²⁹ Gq activates phospholipase C to produce inositol triphosphate (IP3), which causes release of calcium from intracellular stores and activation of myosin light chain kinase causing smooth muscle contraction. Anticholinergics inhibit this cascade and reduce smooth muscle tone by decreasing release of calcium from intracellular stores.

There are two inhaled anticholinergics specifically approved for the treatment of obstructive airway diseases. Ipratropium is classified as a short-acting anticholinergic and is commonly used as maintenance therapy for COPD and as rescue therapy for both COPD and asthmatic exacerbations. It is not indicated for the routine management of asthma. Patients treated with ipratropium experience an increase in exercise tolerance, decrease in dyspnea, and improved gas exchange. Tiotropium is the only long-acting anticholinergic available for COPD maintenance therapy. Tiotropium has been shown to reduce COPD exacerbations, respiratory failure, and all-cause mortality.³⁰

Inhaled anticholinergics are poorly absorbed and therefore serious side effects are uncommon. Most commonly, patients experience dry mouth, urinary retention, and can experience pupillary dilation and blurred vision if the eyes are inadvertently exposed to the drug. Some initial data suggested an increase in cardiovascular and stroke complications with tiotropium; however, additional studies did not consistently demonstrate these complications. In general, anticholinergics are safe and effective treatment for patients with obstructive airway diseases.

Systemic Cholinergic Antagonists

The systemically administered anticholinergics atropine and glycopyrrolate act via the same mechanisms as inhaled anticholinergics. While these anticholinergics can be administered by IV or inhalation, significant systemic absorption occurs and their use is generally limited by side effects. Atropine, in particular, is limited in use because of its tertiary ammonium structure. It has a tendency to cause tachycardia, gastrointestinal upset, blurred vision, dry mouth, and central nervous system effects secondary to its ability to cross the blood–brain barrier. Glycopyrrolate has a quaternary ammonium structure and is insoluble in lipids, similar to ipratropium and tiotropium, and has fewer systemic side effects than atropine. IV glycopyrrolate is also clinically limited in use secondary to side effects.³¹ Glycopyrrolate has been studied as inhaled therapy, however, and is an effective bronchodilator with an intermediate duration of action.^32–35 Clinically, it has never been popular as a mainstay of therapy for obstructive airway diseases.

Influence of Inflammation on the Airway

Asthma and COPD, the most common obstructive airway diseases, have a component of inflammation as part of their pathogenesis. Although inflammation is a common pathogenesis, the characteristics and prominent cellular elements involved in the inflammatory process for each disease are distinct.³⁶ In COPD, neutrophils, macrophages, CD8+ T lymphocytes, and eosinophils are more prominent in the inflammatory composition. In asthma, eosinophils play a more prominent role followed by mast cells, CD 4+ T lymphocytes, and macrophages in the inflammatory composition. Inflammatory cell types present in sputum, biopsy specimens, and bronchoalveolar lavage fluid can help predict the response to antiinflammatory therapy. For example, eosinophilia in induced sputum of a patient presenting with a COPD exacerbation predicts an increase in steroid responsiveness.^37,38 Patients presenting to the operating room with obstructive airway diseases have a high likelihood of taking one of the antiinflammatory therapies in Table 25-2 for control of their disease.

Inhaled Corticosteroids

In the treatment of asthma, the use of inhaled corticosteroids (ICS) reduces the inflammatory changes associated with the disease, thereby improving lung function and reducing exacerbations that result in hospitalization and death.^39–41 On the contrary, the use of ICS as monotherapy in COPD is discouraged. In COPD, ICS are used as a part of combination therapy along with long-acting β-adrenergic agonists (LABA). The combination of drugs acts synergistically and is useful for reducing inflammation. Currently, combination therapy of ICS and LABA is recommended for use in severe to very severe COPD.⁴² The glucocorticoid receptor alpha (GRα) located in the cytoplasm of airway epithelial cells is the primary target of ICS.^43,44 Passive diffusion of steroids into the cell allows for binding of the steroid ligand to GRα, dissociation of heat shock proteins, and subsequent translocation to the nucleus. The complex can bind to promoter regions of DNA sequences and either induce or suppress gene expression. Additionally, the steroid-receptor complex can interact with transcription factors already in place, such as the ones responsible for proinflammatory mediators, without binding to DNA and repress expression of those genes. The steroid-receptor complex also can affect chromatin structure by association with transcription factors that influence the winding of DNA around histones, reducing access of RNA polymerase and other transcription factors, and thus reducing expression of inflammatory gene products.

ICS are used in asthma as part of a multimodal treatment regimen and are added to a therapeutic regimen when there is an increase in severity or frequency of asthma exacerbations. There is good evidence to show that ICS can reduce both hospitalizations and death in asthma. The use of ICS in COPD is limited to use in severe to very severe COPD and in combination with LABA. Although no improvement in mortality has been consistently demonstrated with combination therapy (ICS/LABA), there are reported improvements in health status and lung function along with a reduction in exacerbations.

Side effects have been reported with the use of ICS in asthma and COPD. A meta-analysis reported an increase in pneumonia and serious pneumonia but not deaths when ICS was used in the treatment of COPD.⁴⁵ Other reported side effects in COPD and asthma include oropharyngeal candidiasis, pharyngitis, easy bruising, osteoporosis, cataracts, elevated intraocular pressure, dysphonia, cough, and growth retardation in children. As with any pharmacotherapy, the risks and benefits of therapy must be weighed, and the patient must be carefully monitored for adverse effects. This is especially true with the use of ICS in obstructive lung diseases.

Systemic Corticosteroids

Systemic corticosteroids given in IV or oral form are used for treatment of asthma and COPD exacerbations. The mechanism of action is the same as it is for ICS, activation or suppression of gene products at a transcriptional level and alteration of chromatin structure. Patients that are hospitalized with a COPD exacerbation will typically receive IV corticosteroids to suppress any inflammatory component that may be contributing to the flare up. A study done at the Veterans Affairs medical centers in the United States published in 1999 reported that corticosteroid therapy shortened hospital length of stay and improved forced expiratory volume in 1 second versus placebo.⁴⁶ The study also compared a 2-week regimen versus an 8-week regimen of corticosteroids and found no difference, concluding that the duration of therapy should last only 2 weeks. In asthma, corticosteroids are recommended for exacerbations that are either severe, with a peak expiratory flow of less than 40% of baseline, or a mild to moderate exacerbation with no immediate response to short-acting β-adrenergic agonists. The recommended duration of therapy is 3 to 10 days without tapering. Alternatively, some patients with asthma and COPD will be receiving long-term oral corticosteroid therapy because their disease is difficult to manage. Side effects of systemic corticosteroids are well described and numerous. Hypertension, hyperglycemia, adrenal suppression, increased infections, cataracts, dermal thinning, psychosis, and peptic ulcers are reported complications of corticosteroid therapy.⁴⁷

Leukotriene Modifiers

Leukotriene modifiers are used for the treatment of asthma. They are prescribed primarily for long-term control in addition to short-acting β-adrenergic agonists or in conjunction with ICS and short-acting β agonists. Leukotriene modifiers are taken by mouth, produce bronchodilatation in hours, and have maximal effect within days of administration. Their role in the management of COPD is not defined.⁴⁸ Arachidonic acid is converted to leukotrienes via the 5-lipoxygenase pathway.⁴⁹ Leukotrienes C₄, D₄, and E₄ are the end products of the pathway and cause bronchoconstriction, tissue edema, migration of eosinophils, and increased airway secretions. Leukotriene modifiers come in two different varieties, leukotriene receptor antagonists and leukotriene inhibitors.⁴⁹ The leukotriene inhibitor zileuton antagonizes 5-lipoxygenase inhibiting the production of leukotrienes.

Leukotriene modifiers improve lung function, reduce exacerbations, and are used as long-term asthma therapy.^50,51 Clinical trials have reported that ICS are superior to leukotriene modifiers for long-term control and should be the first-line choice.^52,53 Leukotriene modifiers provide an additional pharmacologic option for the control of asthma. Addition of leukotriene modifiers to ICS will improve control of symptoms of asthma as opposed to ICS alone.⁵⁴

Leukotriene antagonists are usually well tolerated without significant side effects. Links between Churg-Strauss syndrome and the use of leukotriene antagonists have been reported, but it is not clear whether these reports reflect unmasking of a preexisting condition or whether there is a direct link between the two. Zileuton is known to cause a reversible hepatitis in 2% to 4% of patients.

Mast Cell Stabilizers

Cromolyn sodium and nedocromil are the two agents in this category that are used in the treatment of asthma. These agents are delivered by powder inhaler and are not first-line therapy for asthma. They do provide an alternative treatment when the control of asthma is not optimal on other conventional therapies. Cromolyn sodium and nedocromil stabilize submucosal and intraluminal mast cells.⁵⁵ These drugs interfere with the antigen-dependent release of mediators, such as histamine and slow-reacting substance of anaphylaxis, that cause bronchoconstriction, mucosal edema, and increased mucus secretion.

Systematic reviews of the available literature and consensus statements favor the use of ICS over cromolyn sodium or nedocromil as first-line agents to control symptoms of asthma.⁵⁶ Alternatively, cromolyn sodium and nedocromil may be used as preventative treatment before exercise or known allergen exposure causing symptoms of asthma. There are no major side effects reported with the use of cromolyn sodium and nedocromil. The most commonly reported side effects are gastrointestinal upset and coughing or irritation of the throat.

Methylxanthines

The role of theophylline, a methylxanthine, has changed since the introduction of ICS and LABA. Theophylline was a common choice for the control of asthma and COPD because of its bronchodilatory and antiinflammatory effects.⁵⁷ Currently, theophylline is recommended only as an alternative therapy and is not a first-line choice for asthma or COPD.^58,59 Theophylline acts via multiple pathways causing improvement in symptoms in obstructive lung diseases. Theophylline is a nonselective inhibitor of phosphodiesterase and increases levels of cAMP and cGMP causing smooth muscle relaxation. Antagonism of the A₁ and A₂ adenosine receptors also causes smooth muscle relaxation via inhibition of the release of histamine and leukotrienes from mast cells, another reported action of theophylline. In asthma, theophylline reduces the number of eosinophils in bronchial specimens and, in COPD, reduces the number neutrophils in sputum, having an antiinflammatory effect in both conditions. In addition, theophylline activates histone deacetylase and reduces the expression of inflammatory genes. Theophylline and aminophylline are reported to improve diaphragmatic function; however, data have not demonstrated this effect consistently.⁶⁰

Theophylline has been relegated to an alternative therapy in both asthma and COPD. This has occurred largely because of its significant side effect profile and the subsequent need for monitoring of blood level. Patients that are already on an ICS and a LABA and still have symptoms may benefit from the addition of theophylline, especially if leukotriene modifiers and other alternatives are not tolerated. Theophylline can cause significant and life-threatening side effects if not dosed carefully and monitored appropriately. Side effects tend to be more prominent when blood levels exceed 20 mg/L. The most common side effects include headache, nausea, vomiting, restlessness, abdominal discomfort, gastroesophageal reflux, and diuresis. The most significant side effects include seizures, cardiac arrhythmias, and death. Adverse effects from theophylline may be avoided if the clinician follows the patient carefully, monitors blood levels regularly, and educates the patient on the signs and symptoms of overdose.

Influence of Anesthetics on the Airways

Volatile Anesthetics

Volatile anesthetics have a host of effects on the respiratory system. Volatile anesthetics reduce bronchomotor tone and all commonly used volatile anesthetics (Table 25-3), except desflurane, produce a degree of bronchodilatation that may be helpful in patients with obstructive lung disease or in patients that experience any degree of bronchoconstriction.⁶¹ Rooke and colleagues⁶² in 1997 reported that sevoflurane produced a greater reduction in respiratory system resistance than isoflurane or halothane. Volatile anesthetics likely induce bronchodilation by decreasing intracellular calcium, partly mediated by an increase in intracellular cAMP and by decreasing the sensitivity of calcium mediated by protein kinase C.⁶³ The effect is seen to a greater degree in distal airway smooth muscle secondary to the T-type voltage-dependent calcium channel, which is sensitive to volatile anesthetics.⁶⁴

Volatile anesthetics are administered to provide amnesia and blunt the response to surgical stimulation but can be of use in patients that have obstructive airway diseases or experience bronchoconstriction in the operating room. Multiple case reports provide examples of how volatile agents were used solely for the treatment of status asthmaticus.^65–68 The main concern with the use of volatile anesthetics is the rare occurrence of malignant hyperthermia. Hypotension can also be a concern with volatile anesthetics; however, the blood pressure is usually easily restored with small amounts of vasopressors. Deep levels of anesthesia associated with high concentrations of volatile anesthetics may be undesirable, and prolonged administration outside the operating room is problematic.

Intravenous Anesthetics

IV anesthetics can decrease bronchomotor tone when used for induction or IV anesthesia in the operating room. Ketamine, propofol, and midazolam (see Table 25-3) have relaxant effects on airway smooth muscle.⁶⁹ Etomidate and thiobarbiturates do not affect bronchomotor tone to the same extent.⁷⁰ The choice of IV anesthetics for induction and maintenance of anesthesia may be important for a patient with reactive airway disease. The mechanism of reduction of bronchomotor tone for the IV anesthetics is largely unknown. Ketamine is thought to have a direct relaxant effect on smooth muscle.⁷¹ Propofol is thought to reduce vagal tone and have a direct effect on muscarinic receptors by interfering with cellular signaling and inhibiting calcium mobilization.^72,73 The preservative metabisulfite in propofol prevents the inhibition of vagal-mediated bronchoconstriction.⁷⁴

Choosing an agent such as propofol or ketamine can be beneficial in patients with bronchospasm or obstructive airway disease. The use of these IV agents for induction or maintenance of anesthesia over other agents can be useful in minimizing the intraoperative effects of bronchospasm. Although each of the IV anesthetics carries a unique side effect profile, the major effects are not related to the airway. The use of ketamine is associated with increased salivation and coadministration of a small dose of anticholinergic can attenuate secretion production. Propofol is associated with hypotension that usually is easily corrected with vasopressors.

Local Anesthetics

Local anesthetics are primarily used to suppress coughing and blunt the hemodynamic response to tracheal intubation.^75,76 Although animal models have demonstrated some ability of local anesthetics to relax bronchial smooth muscle, in clinical practice the use of local anesthetics as pure bronchodilators is limited by toxicity and the ready availability of more potent bronchodilators such as short-acting β-adrenergic agonists.

Influence of Adjunctive Agents on the Airway

Helium (administered as a mixture of helium and oxygen [heliox]) has the advantage of having a low Reynolds’ number and less resistance during turbulent airflow especially in large airways (see Chapter 24). A trial in patients with COPD exacerbations failed to demonstrate a statistically significant reduction in the necessity for endotracheal intubation in patients treated with noninvasive ventilation and helium-oxygen mixtures.⁷⁷ Helium-oxygen mixtures may be useful as short-term temporizing therapy to decrease the work of breathing in patients with upper airway obstruction. The use of helium-oxygen mixtures is limited by a progressive reduction in efficacy at higher inspired oxygen concentrations.

Antihistamines: Histamine release from mast cells and basophils is responsible for airway inflammation and bronchoconstriction in asthma.⁷⁸ Antihistamines are not standard therapy for asthma, but the use of antihistamines and leukotriene modifiers for allergen-induced bronchoconstriction has shown promise for diminishing the early and late responses to allergens.^78,79 Patients that have allergen-induced asthma or patients that experience an allergic reaction in the operating room may benefit from antihistamines to attenuate the role that histamine plays in bronchoconstriction.

Magnesium sulfate is not standard therapy for asthma exacerbations. Magnesium sulfate is thought to produce additional bronchodilation when given in conjunction with standard therapy for asthma exacerbations. Currently, IV magnesium therapy is reserved as an alternative therapy when the patient has not responded to standard therapy.⁸⁰ The combination of nebulized magnesium sulfate and β-adrenergic agonists have also been studied and show potential benefit in asthma exacerbations.⁸¹ Overall, magnesium sulfate, IV or nebulized, is not a first-line therapy for asthma exacerbations and should be reserved for situations when the patient is not responding to conventional therapy.

Pharmacology of the Pulmonary Circulation

Patients with pulmonary hypertension (PHTN) are high-risk candidates for both cardiac and noncardiac surgery. They have poor cardiorespiratory reserve and are at risk of having perioperative complications including pulmonary hypertensive crises with resultant heart failure, respiratory failure, and dysrhythmias.^82,83 Anesthetic management of these patients can be complex and challenging. Drugs affecting the pulmonary vascular bed are routinely administered during anesthesia, and their effects are of particular interest in patients with PHTN. Reducing the consequences of an elevated pulmonary vascular resistance and the resulting right ventricular dysfunction should be considered as the primary goal of therapy with pulmonary vasodilators. Owing to the contractile properties of the naive right ventricle, attempts at improving its contractility are generally not effective. Therefore, principles of management of PHTN center on reducing right ventricular afterload while preserving coronary perfusion by avoiding reductions in systemic blood pressure.⁸⁴

Anesthetic Drugs

Evaluating the effects of anesthetic drugs on the pulmonary vasculature is challenging. In clinical practice and research, these drugs are rarely administered in isolation. Their administration can lead to concurrent changes in nonpulmonary hemodynamic parameters such as cardiac output (CO) that ultimately affect pulmonary artery pressure (PAP). An increase in PAP may be the result of increased pulmonary vascular resistance (PVR), increased CO, or an increase in left atrial pressure (LAP) (PAP = [PVR × CO] + LAP). In addition, general anesthesia involves manipulation of variables that affect PVR, including fraction of inspired oxygen (FIO₂), carbon dioxide (CO₂), and positive pressure ventilation (PPV).

Ketamine

Historically, ketamine has occupied a controversial position in anesthesia for patients with PHTN. Despite its current widespread use in these challenging patients, it has been classically taught that ketamine causes pulmonary vasoconstriction and should be used with extreme caution in this group. The mechanism of action of ketamine is not fully elucidated. It is an N-methyl-D-aspartic acid (NMDA) receptor antagonist and also binds to opioid receptors and muscarinic receptors.⁸⁵ It appears to stimulate release as well as inhibit neuronal uptake of catecholamines which may account for its cardiostimulatory and bronchodilatory effects. Some animal studies have shown an endothelium-independent vasodilatory response to ketamine in the pulmonary bed.

The effects of ketamine on the human pulmonary vasculature appear to be complex and the clinical literature reveals a vast heterogeneity in regard to results. Factors known to affect pulmonary vasoreactivity such as FIO₂, CO₂, presence of PHTN, and presence of premedicants are not reported or acknowledged in many studies. The hemodynamic effects of a bolus of ketamine can be attenuated or abolished with premedicants such as droperidol, dexmedetomidine, or benzodiazepines.⁸⁶ Early study of the drug’s hemodynamic profile in adult patients showed increases of PAP and PVR in the range of 40% to 50%. This, combined with increases in variables contributing to myocardial oxygen consumption, raised concern about the use of ketamine in patients with coronary artery disease (CAD) and PHTN. More recently in the pediatric literature, Williams et al.⁸⁷ showed no change in PVR or mean pulmonary artery pressure (mPAP) after ketamine administration in spontaneously breathing children with severe PHTN undergoing cardiac catheterization. In another pediatric study, ketamine maintained pulmonary to systemic blood flow and did not affect pulmonary pressure or resistance in children with intracardiac shunt undergoing cardiac catheterization. Propofol, on the other hand, decreased systemic vascular resistance (SVR) leading to increased right to left shunting.⁸⁸ In adult patients undergoing one-lung ventilation (OLV) for lung resection, ketamine did not significantly increase PAP or PVR compared to enflurane. Other case reports highlight the value of the relative cardiostability of the drug in patients with minimal cardiorespiratory reserve.^89,90 Many clinicians incorporate this drug into their routine inductions for patients with severe PHTN (e.g., pulmonary endarterectomy or lung transplantation). The advantages, in particular maintenance of stable hemodynamics and coronary perfusion pressure, seem to outweigh the potential disadvantages.

Propofol

Propofol is commonly used in anesthesia, including for patients with PHTN. It is frequently used to maintain anesthesia during and after lung transplantation. The effects of propofol are thought to be primarily mediated by γ-aminobutyric acid (GABA) receptors. The concerning hemodynamic effect of propofol in the context of PHTN is a decrease in SVR, which can not only have effects on intracardiac shunting, if present, but can lead to decreased coronary artery perfusion of the right ventricle and resultant right ventricular dysfunction. In regard to direct effects on the pulmonary vasculature, animal studies have shown that during increased tone conditions in the pulmonary vasculature, propofol may act as a pulmonary vasoconstrictor.⁹¹ Propofol has also been shown to interfere with acetylcholine-induced pulmonary vasodilation in dogs.⁹² On the other hand, in isolated pulmonary arteries from human and chronically hypoxic rats, etomidate and to a lesser extent propofol showed vessel relaxation.⁹³ The clinical significance of these contradictory results is unknown.

Etomidate

Etomidate is an imidazole that mediates its clinical actions primarily at GABA A receptors. As mentioned earlier, it appears to have vasorelaxant properties in isolated pulmonary arteries. Its major attribute as an induction agent is its stable hemodynamic profile. In patients with cardiac disease, an induction dose of etomidate increased mean arterial pressure (MAP), decreased SVR, and decreased PAP.⁹⁴ In pediatric patients without PHTN presenting for cardiac catheterization, there was no significant change in any hemodynamic parameters after induction with etomidate.⁹⁵

Opioids

Opioids seem to have little to no deleterious effects on the pulmonary vascular system. In anesthetized cats, administration of morphine, fentanyl, remifentanil, and sufentanil caused a vasodilatory response under elevated tone conditions in isolated lobar artery.⁹⁶ The mechanism seems to involve histamine- and opioid-mediated receptor pathways. Clinical experience would echo the cardiostability of judicious narcotic administration in hemodynamically fragile patients.

Volatile Anesthetics

At clinically relevant concentrations, modern volatile anesthetics likely have little to no direct vasodilating effect on the pulmonary vasculature. In pigs, sevoflurane administration depressed right ventricular function with no change in PVR.⁹⁷ This suggests that the decreases in PAP observed with volatile anesthetics may partially occur secondary to the decreases in CO seen with these agents. Nitrous oxide is typically avoided in patients with PHTN as it is believed to cause pulmonary vasoconstriction, perhaps via release of catecholamines from sympathetic nerves supplying the pulmonary vasculature. In patients with mitral stenosis and PHTN presenting for cardiac surgery, administration of nitrous oxide after fentanyl anesthesia (7.5 to 10 µg/kg) increased PVR, PAP, and cardiac index (CI).⁹⁸ However, a subsequent study showed that in the presence of high-dose fentanyl (50 to 75 µg/kg), 70% nitrous oxide is actually was associated with a decrease in PAP and CO in patients with secondary PHTN, with no echocardiographic changes in right ventricular function.⁹⁹

Neuromuscular Blockers

Pancuronium increases PAP in dogs with lung injury.¹⁰⁰ It is theorized to do so indirectly by increases in CO and directly by increasing PVR, possibly by its antagonist actions at muscarinic receptors in the pulmonary vasculature. Rocuronium, cisatracurium, and vecuronium have little to no effect on most cardiac indices in patients undergoing coronary artery bypass graft (CABG).¹⁰¹

Magnesium

Magnesium is a vasodilator in both the systemic and pulmonary circulations. The mechanism of action of magnesium’s effects on vasodilation is likely through its effects on membrane channels involved in calcium flux and through its action in the synthesis of cAMP. It would appear to be an important cofactor for endothelial-dependent pulmonary vasodilation. It has been used successfully to wean NO in PHTN.¹⁰² Increasing doses of magnesium in piglets with acute embolic PHTN decreased mPAP, increased CO, and decreased PVR.¹⁰³ Magnesium has been used to treat persistent PHTN of the newborn, but controversy surrounds its use.

Regional Analgesia

Pain can increase PVR.¹⁰⁴ Perioperative thoracic epidural analgesia (TEA) is commonly used in abdominal and thoracic surgery. TEA may decrease PAP through decreases in CO or via attenuation of the pulmonary sympathetic outflow. In pigs, TEA depresses right ventricular function in acute PHTN.¹⁰⁵ Unilateral thoracic paravertebral block with lidocaine has been shown to decrease myocardial contractility up to 30% and significantly decrease systemic pressure; an effect that may be attenuated by epinephrine. In general, the potential benefits of regional anesthesia in thoracoabdominal surgery typically outweigh the risks of hypotension and right ventricular dysfunction. As with most anesthetic interventions in patients with PHTN, careful titration and monitoring is paramount. A few reports illustrate successful use of epidural analgesia in this patient population.¹⁰⁶

Vasopressors and Inotropes

Vasopressors and inotropes are commonly required during anesthesia to counteract the effects of cardiodepressant and vasodilating drugs. Treatment of hypotension in these patients can be difficult to manage given the typical cautious fluid administration most patient populations.

The innervation and receptor content of the pulmonary vasculature is complex. Neurotransmitter receptors in this system include those from the adrenergic, cholinergic, and dopaminergic families as well as histamine, serotonin, adenosine, purines, and peptides. The pulmonary vasculature’s response to sympathetic activation will generally result in an increase in PVR. In human pulmonary artery, administration of acetylcholine induces pulmonary relaxation.¹⁰⁷

The response of the pulmonary system to exogenous vasopressor administration is dependent on the clinical situation. Consequently, results of studies are heterogeneous. In anesthetized dogs without PHTN, dopamine, epinephrine, norepinephrine, and phenylephrine all increase PAP to varying degrees by varying mechanisms but with no drug is there a significant increase in PVR.¹⁰⁸ Dopamine does not increase PVR after lung transplantation in pigs.¹⁰⁹ In anesthetized patients with chronic secondary PHTN undergoing cardiac surgery, both norepinephrine and phenylephrine increase PAP and PVRI with minimal change in CI.¹¹⁰ Within the clinically relevant MAP target in this study, norepinephrine decreased the mPAP to MAP ratio, but phenylephrine did not, suggesting it may be a better choice in this patient cohort. In a dog model of acute PHTN, however, phenylephrine restored perfusion to the ischemic right ventricle and therefore increased CO.¹¹¹ This is a relevant observation, as it illustrates the importance of coronary artery perfusion in the setting of right ventricular strain and that maintenance of systemic pressure by whatever method may be the most important principle in this subset of patients.

Vasopressin has also been studied. In a chronic hypoxic rat model, vasopressin administration resulted in a V1 receptor–mediated pulmonary vasodilation.¹¹² In an acute PHTN model in dogs, vasopressin increased PVR and resulted in a substantial decrease in right ventricular contractility.¹¹³ Human studies of effects of vasopressin on the pulmonary vasculature are limited. Vasopressin has been used successfully after cardiac surgery in patients with PHTN and resistant hypotension.¹¹⁴ The use of vasopressin to treat acute right ventricular failure in patients with IPPH has been described in obstetric anesthesia.¹¹⁵

Pulmonary Vasodilators

Pulmonary vasodilators are typically employed to improve right ventricular function in the setting of PHTN or in an effort to enhance regional pulmonary blood flow and improve intrapulmonary shunt. In the acute care setting, however, it is these agent’s pulmonary vasodilatory effects that are being exploited. In general, parenteral and oral vasodilators are hampered by their relatively nonselective actions in the pulmonary vascular bed. In addition to their hypotensive systemic hemodynamic effects, their use may also lead to perfusion of underventilated alveoli, worsen intrapulmonary shunt and, in turn, worsen oxygenation. The ideal pulmonary vasodilator should have a rapid onset of action, a short half-life, and produce regional pulmonary vasodilation. This would avoid systemic hypotension and the potential adverse effects on ventilation-perfusion matching that limit the use of systemic agents in critically ill patients. In this regard, inhaled vasodilators are attractive as they preferentially dilate ventilated alveoli and have less systemic effects.

Nitric Oxide

Inhaled nitric oxide (iNO) is preferentially delivered to ventilated lung units leading to improved perfusion to alveoli that are able to participate in gas exchange. This “selective effect” leads to a decrease in intrapulmonary shunt. Medical grade NO may be administered either noninvasively (via a face mask) or through a ventilator circuit. If administered through a circuit, a device is used that can regulate the concentration of NO and monitor levels of nitrogen dioxide—a by-product of NO when it combines with oxygen (Fig. 25-1). At present, iNO is only approved for infants with respiratory distress syndrome. This approval stems from large prospective placebo-controlled studies demonstrating that NO reduced the need for extracorporeal membrane oxygenation (ECMO) and reduced the requirement for oxygen therapy following intensive care unit (ICU) discharge.¹¹⁶ Although there is controversy about a dose-response relationship for NO and pulmonary vasodilation, the typical dose ranges from 10 to 40 ppm. Methemoglobin levels need to be monitored when NO is administered for more than 24 hours. Heart and lung transplantation represent two distinct areas where acute pulmonary vasodilation has strong theoretic benefit as it relates to improving acute right ventricular failure and attenuating reperfusion injury, respectively. The acute right ventricular failure complicating heart transplantation may be attenuated with the use of a pulmonary vasodilator. Although several studies suggest that NO may be useful preoperatively in risk-stratifying patients scheduled for cardiac transplant, only case series support the use of inhaled NO to reverse the right ventricular dysfunction following cardiac transplant. However, based on clinical experience, inhaled NO has become a standard of care in many transplant centers. The beneficial immune-modulating effects of inhaled NO in addition to its vasodilating properties were felt to be responsible for preliminary studies of using inhaled NO to prevent primary graft dysfunction (PGD) after lung transplantation.¹¹⁷ Although a randomized clinical trial failed to show benefit in preventing PGD, it is commonly used to treat the hypoxemia and PHTN seen in established, severe PGD.¹¹⁸ Owing to the inherent cost of using inhaled NO, other pulmonary vasodilators have been evaluated.

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