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Respiratory Distress Joseph Stephan Stapczynski  GENERAL APPROACH TO RESPIRATORY DISTRESS INTRODUCTION AND DEFINITIONS Dyspnea is a feeling of difficult, labored, or uncomfortable breathing, often described as “shortness of breath, ” “breathlessness, ” or “not getting enough air. ”1-3 Dyspnea is usually caused by pulmonary or cardiac disease. Tachypnea is rapid breathing. Orthopnea is dyspnea in the recumbent position; it is most often the result of left ventricular failure but can be seen with diaphragmatic paralysis or chronic obstructive pulmonary disease. Paroxysmal nocturnal dyspnea is orthopnea that awakens the patient from sleep, prompting an upright posture in order to resolve breathlessness. Trepopnea is dyspnea associated with lying on one side (lateral decubitus position) but not the other side. Trepopnea can occur when one lung is more diseased than the other and the patient lies on the side of the more affected lung where gravity increases blood flow to the worse lung and reduces it to the better lung. 4 Platypnea is the opposite of orthopnea: dyspnea in the upright position. Platypnea results from the loss of abdominal wall muscular tone and, in rare cases, from right-to-left intracardiac shunting as occurs from a patent foramen ovale. Hyperpnea is essentially hyperventilation and is defined as minute ventilation in excess of metabolic demand. Respiratory distress is a term used by the physician, combining the patient’s subjective sensation of dyspnea with signs indicating difficulty breathing. Ventilatory or respiratory failure occurs when the lungs and ventilatory muscles cannot move enough air in and out of the alveoli to adequately oxygenate arterial blood and eliminate carbon dioxide. PATHOPHYSIOLOGY Dyspnea is a complex sensation from multiple pathophysiologic mechanisms. 1 Sensory information about respiratory activity gen erated by multiple afferent receptors integrates within the CNS at both the subcortical and cortical levels. The sensation of dyspnea occurs when imbalance exists among the inspiratory drive, efferent activity to the respiratory muscles, and feedback from these afferent receptors. CLINICAL FEATURES Dyspnea is a feature of several disorders seen in the ED ( Table 62-1).5-8 Physical signs associated with dyspnea include tachypnea and tachycardia; use of the accessory respiratory muscles, including the sternocleidomastoid, sternoclavicular, and intercostals; nasal flar ing; inability to speak normally as a consequence of breathlessness; agitation or lethargy as a consequence of hypoxemia; depressed consciousness due to hypercapnia; and paradoxical abdominal wall movement when the abdominal wall retracts inward with inspiration, indicating diaphragmatic fatigue. 2,9 HISTORY AND EXAMINATION Assess the patient for signs of respiratory failure (altered conscious, inability to speak, diaphoresis, inspiratory retractions, nasal flaring, paradoxical respirations) and hypoxemia (using a pulse oximeter). Administer supplemental oxygen if the patient is hypoxemic. Ask about prior diagnosis and treatment of heart or lung disease. Question patients who require daily medications for symptom control about compliance and possible drug interactions. Ask about recent infectious and environmental exposures that may impair respiratory function. Dyspnea is a prominent symptom of acute heart failure, and differentiating heart failure from pulmonary causes of dyspnea is occasionally difficult.

ications for symptom control about compliance and possible drug interactions. Ask about recent infectious and environmental exposures that may impair respiratory function. Dyspnea is a prominent symptom of acute heart failure, and differentiating heart failure from pulmonary causes of dyspnea is occasionally difficult. 10 Treatment differs, and embarking down the wrong pathway of treatment can have adverse consequences.11 Several findings can assist in this differentiation, although few of them are definitive by themselves (see Chapter 53, “ Acute Heart Failure”). An S3 gallop on physical examination or pulmonary venous congestion/ interstitial edema (especially with concomitant cardiomegaly) on chest radiograph strongly suggests heart failure as the cause of the dyspnea. The physician’s overall gestalt of the diagnosis, the presence of jugular venous distention on examination, and alveolar edema on chest radio graph together also suggest heart failure, although any one finding is not specific. Wheezing, dyspnea on exertion, orthopnea, paroxysmal noc turnal dyspnea, and leg edema are not useful in discriminating between cardiac and pulmonary causes. Conversely, the absence of these findings does not exclude heart failure.  LABORATORY TESTING AND IMAGING The cause of dyspnea in most ED patients can be identified by the  history, the physical examination, ECG, point of care US, and chest radiograph. Pulse oximetry provides a rapid assessment of arterial oxygen saturation, but is an insensitive screening test for disorders of gas exchange. Arterial blood gas analysis is more sensitive for detecting impaired gas exchange but cannot evaluate the work of breathing. Arterial blood gas testing can find the patient with dyspnea or tachypnea who exhibits no evidence of hypoxemia or pulmonary disease, suggesting hyperventilating from metabolic acidosis. Bedside spirometric analysis (e.g., peak expiratory flow), especially if performed before and after bronchodilator therapy, can diagnose dyspnea resulting from obstructive airway disease. Spirometry requires voluntary effort that might be difficult for dyspneic patients. Negative inspiratory force can assess strength of the diaphragm and inspiratory Pulmonary Disorders SECTION CHAPTER TABLE 62-1 Common Causes of Dyspnea in the ED Most Common Causes Obstructive airway disease: asthma, chronic obstructive pulmonary disease Decompensated heart failure/ cardiogenic pulmonary edema Ischemic heart disease: unstable angina and myocardial infarction Pneumonia Psychogenic Most Immediately Life-Threatening Causes Upper airway obstruction: foreign body, angioedema, hemorrhage Tension pneumothorax Pulmonary embolism Neuromuscular weakness: myasthenia gravis, Guillain-Barré syndrome, botulism Fat embolism Tintinalli_Sec08_p0425-0472.indd 425 8/1/19 2:10 PM

l infarction Pneumonia Psychogenic Most Immediately Life-Threatening Causes Upper airway obstruction: foreign body, angioedema, hemorrhage Tension pneumothorax Pulmonary embolism Neuromuscular weakness: myasthenia gravis, Guillain-Barré syndrome, botulism Fat embolism Tintinalli_Sec08_p0425-0472.indd 425 8/1/19 2:10 PM 426 SECTION 8: Pulmonary Disorders muscles, which is useful in patients with neuromuscular disease to assess respiratory muscle weakness. Bedside lung US can differentiate acute decompensated heart failure from noncardiac causes of acute dyspnea (see Chapter 53, “ Acute Heart Failure”). 14,15 Bedside US can also identify pleural effusion, pneumotho rax, cardiac tamponade, cardiac functional abnormalities, pulmonary consolidation, and intravascular volume status. 16,17 B-type natriuretic peptide (BNP) and d-dimer testing can be useful in evaluating dyspnea in the ED. BNP or its precursor, N-terminal pro-BNP , is elevated with any cause of ventricular overload, including heart failure and strain (both right or left sided), myocardial ischemia, pulmonary embolism, sepsis, or chronic obstructive pulmonary disease (see Chap ter 53, “ Acute Heart Failure”). A normal BNP (<100 picograms/mL) or N-terminal pro-BNP (<300 picograms/mL) excludes heart failure in low and moderate pretest probability patients outside of “flash” pulmonary edema settings. 18 Conversely, a high level (BNP >500 picograms/mL or N-terminal pro-BNP >900 picograms/mL) is moderately useful for establishing the diagnosis of heart failure. BNP values between 100 and 500 picograms/mL have no utility in excluding or including heart failure in the dyspneic patient. 19 Overall, BNP measurement usually is not needed for diagnosis and adds little impactful prognostic information, and it is best used when diagnostic uncertainty is present rather than routinely. A normal d-dimer test can exclude pulmonary embolism in patients with low and moderate pretest probability (see Chapter 56, “Venous Thromboembolism Including Pulmonary Embolism”). TREATMENT In severe dyspnea, the initial treatment goal is maintenance of the airway and oxygenation, seeking an arterial oxygen partial pressure (Pa o 2) >60 mm Hg (>8 kPa) and/or arterial oxygen saturation (Sao2) ≥90%. Next, or in those with lesser dyspnea, treat the underlying disorder. Opioids or benzodiazepines provide comfort for terminal patients with dyspnea.  HYPOXIA AND HYPOXEMIA INTRODUCTION Hypoxia is insufficient alveolar oxygen content or insufficient delivery of oxygen to the tissues. The amount of oxygen available to the tissues is a function of the arterial oxygen content (Ca o 2) comprising a small portion dissolved in plasma and a larger portion bound to hemoglobin: Cao2 = 0.0031 × Pao2 + 1.38 × Hemoglobin × Sao2 Oxygen delivery (D o2) is a product of arterial oxygen content and cardiac output: Do2 = Cao2 × Cardiac output Tissue hypoxia occurs in states of low cardiac output, low hemoglobin concentration, or low Sa o2. The level of oxygen saturation in arterial hemoglobin is, in turn, dependent on the Pao 2, as determined by the oxygen–hemoglobin dissociation curve. Hypoxemia is an abnormally low arterial oxygen tension (defined as a Pa o2 <60 mm Hg or <8 kPa). Although alveolar hypoxia is the most common cause of hypoxemia, hypoxia and hypoxemia are not interchangeable; one can occur without the other. For example, in states of low Pao 2 (hypoxemia) with concomitant polycythemia, the patient may have no tissue hypoxia. Alternatively, severely anemic patients may suffer tissue hypoxia despite a normal Pao 2. Relative hypoxemia is the term used when the arterial oxygen tension is lower than expected for a given level of inhaled oxygen.

tates of low Pao 2 (hypoxemia) with concomitant polycythemia, the patient may have no tissue hypoxia. Alternatively, severely anemic patients may suffer tissue hypoxia despite a normal Pao 2. Relative hypoxemia is the term used when the arterial oxygen tension is lower than expected for a given level of inhaled oxygen. The degree of relative hypoxemia can be assessed by calculating the alveolar–arterial (A-a) oxygen partial pressure gradient, P (A-a)o2, which measures effi ciency of oxygen transfer from the lungs to the circulation. Alveolar oxygen partial pressure calculation uses the inhaled oxygen concentration (21% for room air), atmospheric pressure (760 mm Hg at sea level), and displacement by water vapor (47 mm Hg for full saturation) and carbon dioxide (CO 2). Gas in the alveolus is fully saturated with water vapor, and the amount of alveolar oxygen is further reduced by CO2 that freely diffuses from the pulmonary capillaries in an amount determined by the ratio between oxygen consumption and CO 2 production, termed the respiratory quotient, which is affected by diet. On a typical mixed diet, the respiratory quotient is 0.8. Breathing room air at sea level allows this alveolar formula: Pao 2 = 0.21 × (760 – 47) – Paco 2/0.8 The A-a gradient at sea level for room air is: P(A-a)o2 = 149 – Paco 2/0.8 – Pao 2 A simplified formula often used is: P(A-a)o2 = 145 – Paco 2 – Pao2 A normal P (A-a)o2 is <10 mm Hg in young, healthy patients and increases with age, predicted by the formula: P(A-a)o2 = 2.5 + 0.21 (age in years) (± 11) This normal A-a gradient is for healthy, asymptomatic individuals measured in an upright or sitting position. The supine position and many chronic cardiac or pulmonary diseases may raise the A-a gradi ent. The supine position is a common ED patient position, impairing the assessment. PATHOPHYSIOLOGY Hypoxemia results from any combination of five mechanisms. 1. Hypoventilation. Hypoxemia from hypoventilation alone has an increased Paco 2 and a normal A-a O 2 gradient. The additional CO 2 displaces inhaled oxygen in the alveolus. However, the remaining alveolar oxygen diffuses and mixes normally into the arterial blood, displaying a normal A-a O 2 gradient as long as there is no alveolar or interstitial disease. 2. Right-to-left shunt. Right-to-left shunting occurs when blood enters the systemic circulation without traversing ventilated lung. There is always a small degree of right-to-left shunting because of the direct left atrial return of deoxygenated blood from both the coronary veins and the bronchial arteries. Increased right-to-left shunting occurs in a variety of conditions, including congenital cardiac malformation and acquired pulmonary disorders (pulmonary consolidation, pulmo nary atelectasis). Regardless of the specific cause of the right-to-left shunt, it is always associated with an increase in the A-a O 2 gradient. A hallmark of significant right-to-left shunting is the failure of arterial oxygen levels to increase in response to supplemental oxygen. Although a small improvement may be observed with supplemental oxygen, hypoxemia is never fully eliminated because of the mixing of deoxygenated blood in the systemic circulation. 3. Ventilation-perfusion ( ˙V/ ˙Q) mismatch. Ideal pulmonary gas exchange depends on a balance of ventilation and perfusion. Any abnormality resulting in a regional alteration of either ventilation or perfusion can adversely affect pulmonary gas exchange, resulting in hypoxemia. There are many causes of ˙V/˙Q mismatch, including pulmonary emboli, pneumonia, asthma, chronic obstructive pulmonary dis ease, and even extrinsic vascular compression.

abnormality resulting in a regional alteration of either ventilation or perfusion can adversely affect pulmonary gas exchange, resulting in hypoxemia. There are many causes of ˙V/˙Q mismatch, including pulmonary emboli, pneumonia, asthma, chronic obstructive pulmonary dis ease, and even extrinsic vascular compression. Regardless of cause, hypoxemia from ventilation-perfusion mismatch is associated with an increased A-a O 2 gradient, and hypoxemia improves with supplemental oxygen. Tintinalli_Sec08_p0425-0472.indd 426 8/1/19 2:10 PM

abnormality resulting in a regional alteration of either ventilation or perfusion can adversely affect pulmonary gas exchange, resulting in hypoxemia. There are many causes of ˙V/˙Q mismatch, including pulmonary emboli, pneumonia, asthma, chronic obstructive pulmonary dis ease, and even extrinsic vascular compression. Regardless of cause, hypoxemia from ventilation-perfusion mismatch is associated with an increased A-a O 2 gradient, and hypoxemia improves with supplemental oxygen. Tintinalli_Sec08_p0425-0472.indd 426 8/1/19 2:10 PM CHAPTER 62: Respiratory Distress 427 4. Diffusion impairment. Pulmonary gas exchange requires diffusion across the alveolar–blood barrier. Regardless of the specific cause of the diffusion impairment, the A-a O 2 gradient is increased, and hypoxemia improves with supplemental oxygen. 5. Low inspired oxygen. Decreased ambient oxygen pressure results in hypoxemia. This is commonly seen at high altitude (including commercial air travel) or in nonobstructive asphyxia. The A-a O 2 gradient is normal, and hypoxemia improves with supplemental oxygen. For example, Denver, at 5400 ft (1646 m) above sea level, has an atmo spheric pressure of 620 mm Hg (82.7 kPa) and an inhaled Po 2 of only 0.21 × 620 = 130 mm Hg, as opposed to 160 mm Hg at sea level. There are acute compensatory mechanisms for hypoxemia. Initially, minute ventilation increases. Next, pulmonary arterial vasoconstriction decreases perfusion to hypoxic alveoli. Although vasoconstriction balances ventilation and perfusion to restore arterial oxygenation, it may also cause acute right heart failure and is inef fective with diffuse lung disease. Finally, sympathetic tone increases and improves oxygen delivery by increasing cardiac output, usually with an increased heart rate. Chronic compensatory mechanisms include an increased red blood cell mass and decreased tissue oxygen demands. These compensatory mechanisms appear to be activated at different levels of hypoxemia among different individuals. However, the acute compensatory mechanisms are always activated when Pa o reaches 60 mm Hg (8 kPa), and compensatory mechanisms fail when Pao 2 falls below 20 mm Hg (2.67 kPa). CLINICAL FEATURES CNS manifestations of tissue hypoxia include agitation, headache, somnolence, coma, and seizures. Although tachypnea and hyperventilation are often present, by the time Pa o 2 is <20 mm Hg (<2.67 kPa), there is a central depression of respiration. Cyanosis, the blood or tissue discoloration associated with a lowered arterial oxygenation saturation, is not a sensitive or specific indicator of hypoxemia. Patients with chronic compensatory mechanisms may display polycythemia or alterations in body habitus (e.g., pulmonary cachexia). DIAGNOSIS AND TREATMENT Pulse oximetry accurately predicts significant hypoxemia, although clinically acceptable pulse oximetry saturation readings (>90%) may not exclude hypoxemia. If certain hemoglobin abnormalities exist (e.g., methemoglobin or carboxyhemoglobin), pulse oximetry analysis may overestimate oxygen saturation and underestimate the response to supplemental oxygen (see the section “Cyanosis, ” below). Regardless of the specific cause of hypoxemia, the initial approach remains the same: ensuring a patent airway and providing supplemental oxygenation with a goal of maintaining a Pa o 2 >60 mm Hg (>8 kPa). Except in patients with right-to-left shunts, arterial oxygenation responds to supple mental oxygen.  HYPERCAPNIA INTRODUCTION Hypercapnia is exclusively caused by alveolar hypoventilation and is defined as a Pa co 2 >45 mm Hg (>6 kPa). Alveolar hypoventila tion has many causes, including rapid shallow breathing, small tidal volumes, underventilation of the lung, or reduced respiratory drive. Hypercapnia never results from increased CO 2 production alone (Table 62-2).

y caused by alveolar hypoventilation and is defined as a Pa co 2 >45 mm Hg (>6 kPa). Alveolar hypoventila tion has many causes, including rapid shallow breathing, small tidal volumes, underventilation of the lung, or reduced respiratory drive. Hypercapnia never results from increased CO 2 production alone (Table 62-2). PATHOPHYSIOLOGY A portion of each tidal volume remains in the non–gas-exchange por tion of the respiratory system—termed the dead space —that is deter mined by the anatomic size of the conducting airways (trachea and bronchi). The portion of the tidal volume that reaches the alveoli is that which remains after the dead space volume is subtracted: Ta (alveolar volume) = Vt (tidal volume) – Td (dead space) Alveolar ventilation (Va) per minute is the alveolar volume multiplied by the respiratory rate (R): Va = Ta × R = (Vt – Td) × R Alveolar hypoventilation can result from a decrease in respiratory rate, a decrease in tidal volume, or an increase in dead space. Dead space volume can increase above that due to the anatomic size of the conducting airways when ventilated portions of the lung have deficient or absent perfusion; these ventilated portions do not participate fully in gas exchange because of inadequate blood flow. Medullary chemoreceptors stimulate both respiratory rate and tidal volume in response to increased CO 2, so that alveolar ventilation is finely controlled relative to CO 2 production and Paco 2 is maintained within a narrow range. Decreased respiratory drive is associated with CNS lesions and toxic depression (Table 62-2). Thoracic cage and neuromuscular disorders produce hypoventilation by slowing respiratory rate and/or decreasing tidal volume relative to the production of CO 2. Intrinsic lung diseases, such as chronic obstructive pulmonary disease, produce alveolar hypoventilation because of an increase in dead space. CLINICAL FEATURES The signs and symptoms of hypercapnia depend on the absolute value of Paco 2 and its rate of change. Acute elevations increase intracranial pressure, and patients may have headache, confusion, or lethargy. Severe hypercapnia can trigger seizures and coma. Extreme hypercapnia can result in cardiovascular collapse, but this is usually seen only with acute elevations of Paco 2 >100 mm Hg (>13.3 kPa). As opposed to acute hypercapnia, chronic hypercapnia, even >80 mm Hg (>10.7 kPa), may be well tolerated. DIAGNOSIS Diagnosis of hypercapnia requires arterial blood gas analysis or end-tidal 2 measurement. With acute hypercapnia, the serum bicarbonate level increases slightly as a result of mass action through the CO2–bicarbonate equilibrium: bicarbonate increases about 1 mEq/L for each increase of 10 mm Hg (1.3 kPa) in the Pa co 2. Patients with chronic hypercapnia have an elevated serum bicarbonate concentration and near-normal pH due to the renal retention of bicarbonate in response to increased Paco 2: the serum bicarbonate concentration increases about 3.5 mEq/L for each increase of 10 mm Hg (1.3 kPa) in the Pa co 2. TABLE 62-2 Causes of Hypercapnia •   Depressed central respiratory drive •   Structural CNS disease: brainstem lesions •   Drug depression of respiratory center: opioids, sedatives, anesthetics •   Endogenous toxins: tetanus •   Thoracic cage disorders •   Kyphoscoliosis •   Morbid obesity •   Neuromuscular impairment •   Neuromuscular disease: myasthenia gravis, Guillain-Barré syndrome •   Neuromuscular toxin: organophosphate poisoning, botulism •   Intrinsic lung disease associated with increased dead space •   Chronic obstructive pulmonary disease •   Upper airway obstruction Tintinalli_Sec08_p0425-0472.indd 427 8/1/19 2:10 PM

nt •   Neuromuscular disease: myasthenia gravis, Guillain-Barré syndrome •   Neuromuscular toxin: organophosphate poisoning, botulism •   Intrinsic lung disease associated with increased dead space •   Chronic obstructive pulmonary disease •   Upper airway obstruction Tintinalli_Sec08_p0425-0472.indd 427 8/1/19 2:10 PM 428 SECTION 8: Pulmonary Disorders TREATMENT Hypercapnia is treated by increasing minute ventilation by increasing either the respiratory rate or the tidal volume, or often both, as needed. This involves ensuring a patent airway and may require noninvasive positive-pressure ventilation, mechanical ventilation, the use of an antidote to reverse drug toxicity, or rarely, the use of a respiratory stimulant such as doxapram. 22-24 Do not withhold oxygen required to maintain minimum oxygen saturation levels in any chronic lung disease patient in an effort to stimulate ventilation and reduce hypercapnia. The disposition of hypercapnic patients depends primarily on the underlying cause and severity. In general, hospitalize patients with hypercapnia with new acidosis or that causes CNS symptoms, along with patients with neuromuscular disease, either congenital or acquired, who present with acute hypercapnia. Some chronic obstructive pulmonary disease patients have chronic hypercapnia and do not require admis sion provided they are stable clinically and the arterial pH is normal. Conversely, patients with chronic obstructive pulmonary disease who display worsening hypercapnia or added respiratory acidosis (pH low ered from baseline) despite maximal outpatient therapy require hospital admission.  COUGH INTRODUCTION Cough is a protective reflex for clearing secretions and foreign debris from the tracheobronchial tree. 25 Coughing starts with stimulation of irritant receptors located largely in the larynx, trachea, and major bronchi. These receptors respond to inhaled irritants (e.g., dust), allergens (e.g., ragweed pollen), toxic substances (e.g., gastric acid), hypo- or hyperosmotic liquids, inflammation (e.g., asthma), cold air, instrumentation, and excess pulmonary secretions. Minor cough receptors located in the upper respiratory tract (sinuses and pharynx) and chest (pleura, pericardium, and diaphragm) may stimulate coughing. Signals from these receptors travel by means of the vagus, phrenic, and other nerves to the cough center in the medulla. Once stimulated, the cough center initiates the stereotypical cough pattern: a deep inspiration followed by attempted expiration against a closed glottis that suddenly opens, providing for a forceful exhalation of gas, secretions, and foreign debris from the tracheobronchial tree. The coughing sound is generated at the larynx and resonates in the nasal cavity and the lungs. CLINICAL FEATURES Acute cough is cough lasting <3 weeks and is usually associated with self-limited upper respiratory or bronchial infections ( Table 62-3). Subacute cough lasts 3 to 8 weeks and is most commonly postinfectious, but causes of subacute cough overlap with causes of acute and chronic cough. Chronic cough is present for >8 weeks. 27-29  ACUTE COUGH Acute cough is most often caused by upper respiratory tract infection, lower respiratory tract infection, and allergic reactions. 26 Common upper respiratory infections are often a combination of rhinorrhea, sinusitis, pharyngitis, and laryngitis, with the cough a result of drainage from the nasopharynx onto cough receptors in the pharynx and lar ynx. A productive cough is the hallmark of acute bronchitis. Although pneumonia generally produces a cough, pulmonary secretions may be scant and the cough nonproductive. Pertussis in adults has been associ ated with acute cough lasting 1 to 6 weeks.

nage from the nasopharynx onto cough receptors in the pharynx and lar ynx. A productive cough is the hallmark of acute bronchitis. Although pneumonia generally produces a cough, pulmonary secretions may be scant and the cough nonproductive. Pertussis in adults has been associ ated with acute cough lasting 1 to 6 weeks. 30 The observed increased incidence of pertussis in adolescents and young adults is likely due to waning vaccine immunity with increasing age.  SUBACUTE COUGH Postinfectious cough is the most likely cause of subacute cough. The mechanisms include postviral airway inflammation with bronchial hyperresponsiveness, mucus hypersecretion, upper airway cough syn drome (postnasal discharge), or asthma.  CHRONIC COUGH The most common causes of chronic cough are (1) smoking, often with chronic bronchitis; (2) upper airway cough syndrome (formerly postnasal discharge); (3) asthma; (4) gastroesophageal reflux; and (5) angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy (Table 62-3). 27-29 Smoking-induced coughing is usually worse in the morning and, with chronic bronchitis, usually productive. Upper airway cough syndrome, formerly called postnasal discharge syndrome, is associated with mucus drainage from the nose, a history of “allergies or sinus problems, ” and frequent clearing of the throat or swallowing of mucus. 27 The postnasal drainage itself may not only directly stimulate a cough, but the conditions producing postnasal drainage (e.g., allergic rhinitis) may also cause irritation or inflammation of upper airway structures that directly stimulates cough receptors independently of the drainage. Chronic cough associated with asthma is usually worse at night, exacerbated by irritants, and associated with episodic wheezing and dyspnea. 31 Asthma can be exacerbated by β-blocker therapy and also presents with nocturnal coughing. Cough associated with gastroesophageal reflux often has a history of heartburn, is worse when lying down, and improves with anti-acid therapy (antacids, H 2 blockers, or proton pump blockers).32,33 The incidence of angiotensin-converting enzyme inhibitor–induced cough is approximately 5% to 10% in the Western world, although higher values have been reported in other areas. 34 The observed incidence of angiotensin receptor blocker–induced cough is about 35% to 40% that of angiotensin-converting enzyme inhibitors. 35 Angiotensin-converting enzyme inhibitor–induced cough is thought to result when the blockade of angiotensin-converting enzyme leads to accumulation of bradykinin and substance P , which stimulate the pulmonary cough receptors and enhance the formation of irritating prostaglandin metabolites. Angio tensin-converting enzyme inhibitor–induced cough is highly variable in onset (as early as 1 week to as late as 1 year after starting treatment), severity (only slightly bothersome to debilitating symptoms), and variation during the day. Cough typically resolves in 1 to 4 weeks after angiotensin-converting enzyme or angiotensin receptor blocker therapy is stopped but may linger up to 3 months (see Chapter 14, “ Allergy and Anaphylaxis”). DIAGNOSIS AND TREATMENT Most causes of acute cough do not warrant ancillary tests. A chest radiograph is wise for patients with purulent sputum and/or fever, and spirometry can document the presence of airflow obstruction in patients with asthma; a flow-volume loop can detect vocal cord dysfunction masquerading as recurrent asthma-like wheezing or cough.

of acute cough do not warrant ancillary tests. A chest radiograph is wise for patients with purulent sputum and/or fever, and spirometry can document the presence of airflow obstruction in patients with asthma; a flow-volume loop can detect vocal cord dysfunction masquerading as recurrent asthma-like wheezing or cough. Pertussis is TABLE 62-3 Differential Diagnosis of Cough Acute Chronic Chronic: Less Common Upper respiratory infection: rhinitis, sinusitis, pertussis Lower respiratory tract infection: bronchitis, pneumonia Allergic reaction Asthma Environmental irritants Transient airway hyperresponsiveness Foreign body Smoking and/or chronic bronchitis Upper airway cough syndrome (postnasal discharge syndrome) Asthma: reactive airways disease Gastroesophageal reflux Angiotensin-converting enzyme inhibitor Angiotensin II receptor blocker Postinfectious; pertussis Heart failure Bronchiectasis Lung cancer or other intrathoracic mass Emphysema Occupational and environmental irritants Recurrent aspiration or chronic foreign body Psychiatric Miscellaneous: cystic fibrosis, interstitial lung disease Tintinalli_Sec08_p0425-0472.indd 428 8/1/19 2:10 PM

blocker Postinfectious; pertussis Heart failure Bronchiectasis Lung cancer or other intrathoracic mass Emphysema Occupational and environmental irritants Recurrent aspiration or chronic foreign body Psychiatric Miscellaneous: cystic fibrosis, interstitial lung disease Tintinalli_Sec08_p0425-0472.indd 428 8/1/19 2:10 PM CHAPTER 62: Respiratory Distress 429 a clinical diagnosis in patients with subacute cough as the commonly available culture, and polymerase chain reaction tests have decreasing sensitivity after the third week of coughing.  ACUTE COUGH In addition to disease-specific therapy,37 patients with acute cough may benefit from antitussives. 38,39 Demulcents, part of most proprietary cough preparations, soothe the pharynx and modestly alter the cough reflex. Of the herbal agents, menthol and the pungent spices (e.g., pep per, mustard, garlic, radish, and onions) have an antitussive effect. Naproxen reduces coughing in patients with acute bronchitis. 41 In both children and adults, acute coughing illnesses can last up to 3 weeks. 42,43 For intractable coughing paroxysms in the ED, some patients respond to 4 mL of 1% or 2% preservative-free lidocaine (40 or 80 milligrams) by nebulization. This will cause transient suppression of the gag reflex due to posterior pharyngeal anesthesia.  SUBACUTE AND CHRONIC COUGH Determine if the subacute cough is postinfectious—one following a recent respiratory infection. If postinfectious, then assess for transient bronchial hyperresponsiveness, asthma, pertussis, upper airway cough syndrome, pneumonia, or an acute exacerbation of chronic bronchitis. Treatment is then directed at the presumed cause. If subacute cough is not postinfectious, it is evaluated and treated in the same manner as a chronic cough. Chronic cough is most often the result of a few common disorders, so an algorithmic approach to treatment using sequential steps is recom mended (Table 62-4). 44,45 For patients with refractory chronic cough, moderate reduction in cough severity has been observed with opioid antitussives, dextro methorphan, moguisteine, gabapentin, and pregabalin.46,47  HICCUPS INTRODUCTION Hiccup, or singultus, is an involuntary spastic contraction of the inspiratory muscles. Hiccups have no specific protective purpose. 48 The afferent arm of the hiccup reflex consists of the phrenic and vagus nerves as well as the thoracic sympathetic chain. Normally, glottis closure inhibits inspiration and prevents aspiration during swallowing. Conversely, inspiration normally inhibits glottic closure and maintains an open airway. The hiccup reflex disrupts the connection between these two processes so that 30 to 40 milliseconds after the onset of inspiration, glottic closure is stimulated. In most cases in which a specific cause can be assigned, hiccups appear to result from stimulation, inflammation, or injury to one of the nerves of the reflex arc. CLINICAL FEATURES Hiccups are classified as benign and self-limited when they last for <48 hours, persistent if present for >48 hours, and intractable if they last longer than a month ( Table 62-5). Benign hiccups are generally initiated by gastric distention from food, drinking (especially carbonated beverages), or air. Alcohol inges tion appears to precipitate hiccups by relaxing the relationship between inspiration and glottic closure, making it easier for other stimuli to trigger the reflex. Persistent hiccups are usually a result of injury or irritation to a branch of the vagus or phrenic nerves. One rare but readily treatable stimulus is a foreign body (often a hair) in the external auditory canal that is pressing against the tympanic membrane and stimulating the auricular branch of the vagus nerve.

lex. Persistent hiccups are usually a result of injury or irritation to a branch of the vagus or phrenic nerves. One rare but readily treatable stimulus is a foreign body (often a hair) in the external auditory canal that is pressing against the tympanic membrane and stimulating the auricular branch of the vagus nerve. Several drugs (e.g., dexamethasone and chemotherapeutic agents) are implicated in inducing hiccups. DIAGNOSIS AND TREATMENT Determine if a specific triggering event exists (Table 62-5). Ask if the hiccups persist during sleep; resolution during sleep suggests a psy chogenic cause, although this distinction is not absolute. Look in the external auditory canal for a foreign body. Obtain a chest radiograph for patients with chronic hiccups. Fluoroscopy can evaluate for unilateral versus bilateral diaphragmatic movement during hiccups but is not part of the ED evaluation. Unilateral movement suggests focal injury to the phrenic nerve on the affected side. A variety of physical maneuvers and medications have been used to terminate an acute episode of hiccups ( Table 62-6). 51-53 Many of these physical maneuvers are based on the concept that stimulating the pharynx will block the vagal portion of the reflex arc and abolish the hiccups. 51 No one method appears to be more effective than another. Swallowing a teaspoon of dry granulated sugar is about as effective as others and does not involve the infliction of noxious or painful stimulation. Drug treatment for persistent hiccups (Table 62-7) is believed to work by inhibiting the reflex arc. 52,53 Several agents are described as effective, but only chlorpromazine has U.S. Food and Drug Administration approval for treatment of intractable hiccups. Chlorpromazine and metoclopramide take effect within 30 minutes. Adverse effects include extrapyramidal symptoms with both agents and hypotension with chlorpromazine. Nifedipine, valproic acid, baclofen, and gabapentin are options usually started by the primary care physician if the hiccups do not respond to chlorpromazine or metoclopramide. TABLE 62-4 Sequential Approach to Chronic Cough •   Obtain chest radiograph, if not already done. •   Reduce exposure to lung irritants (e.g., smoking) and discontinue angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and β-blockers. •   Treat for postnasal discharge with an oral first-generation antihistamine/decongestant with or without an inhaled nasal steroid. If the cough improves, continue treatment and consider evaluating for sinus disease with imaging studies. •   Evaluate for bronchospasm with spirometry (include flow-volume loop to detect vocal cord dysfunction) with or without methacholine provocation; if positive, treat with inhaled bronchodilators and corticosteroids if lower source identified. •   Treat for gastroesophageal reflux with lifestyle changes, H2 blockers, or proton pump inhibitors. •   If cough persists, obtain CT scan of the chest, especially if patient is a smoker and cough persists despite smoking cessation. •   If cough persists, consider referral to otolaryngologist for laryngoscopy, gastroenterologist for endoscopy and/or esophageal pH monitoring, or pulmonologist for bronchoscopy.

ibitors. •   If cough persists, obtain CT scan of the chest, especially if patient is a smoker and cough persists despite smoking cessation. •   If cough persists, consider referral to otolaryngologist for laryngoscopy, gastroenterologist for endoscopy and/or esophageal pH monitoring, or pulmonologist for bronchoscopy. TABLE 62-5 Differential Diagnosis of Consequence: Hiccups Acute: Benign, Self-Limited Gastric distention Alcohol intoxication Excessive smoking Abrupt change in environmental temperature Psychogenic Chronic: Persistent, Intractable CNS structural lesions Vagal or phrenic nerve irritation Metabolic: uremia, hyperglycemia General anesthesia Surgical procedures: thoracic, abdominal, prostate and urinary tract, craniotomy Foreign body in ear touching tympanic membrane (especially hair) TABLE 62-6 Treatment of Hiccups: Physical Maneuvers •   Remove foreign body from ear •   Swallow a teaspoon of sugar •   Sip ice water •   Drink water quickly Tintinalli_Sec08_p0425-0472.indd 429 8/1/19 2:10 PM

inal, prostate and urinary tract, craniotomy Foreign body in ear touching tympanic membrane (especially hair) TABLE 62-6 Treatment of Hiccups: Physical Maneuvers •   Remove foreign body from ear •   Swallow a teaspoon of sugar •   Sip ice water •   Drink water quickly Tintinalli_Sec08_p0425-0472.indd 429 8/1/19 2:10 PM 430 SECTION 8: Pulmonary Disorders  CYANOSIS INTRODUCTION Cyanosis is a bluish color of the skin and mucous membranes resulting from an increased amount of reduced hemoglobin (deoxyhemoglobin) or hemoglobin derivatives. 54 The detection of cyanosis is subjective and is not a sensitive indicator of the state of arterial oxygenation; cyanosis is determined by the absolute amount of deoxygenated hemoglobin in the blood, not the amount of oxygenated hemoglobin. Cyanosis is divided into central or peripheral categories (Table 62-8). Central cyanosis is cyanosis of the mucous membranes and tongue due to inadequate pulmonary oxygenation or an abnormal hemoglobin. Peripheral cyanosis is cyanosis of the fingers or extremities from vasoconstric tion and diminished peripheral blood flow. All conditions that cause central cyanosis also result in peripheral cyanosis. CLINICAL FEATURES Cyanosis is usually visible when deoxygenated hemoglobin exceeds 5 grams/dL (50 grams/L), but individuals with sensitive vision in ideal circumstances may detect central cyanosis with deoxyhemoglobin concentration as low as 1.5 grams/dL (15 grams/L). Various physiologic, anatomic, and physical factors other than the amount of reduced hemoglobin may influence the appearance of cyanosis, making an accurate clinical detection of the degree or even the presence of cyanosis difficult (Table 62-9). The tongue and buccal mucosa are sensitive sites for observing central cyanosis. Peripheral cyanosis is caused by the slowing of blood flow to an area and an abnormally large extraction of oxygen from normally saturated arterial blood. Peripheral vascular disease, shock states, heart failure, and cold exposure all create states of vasoconstriction and decreased peripheral blood flow, with cyanosis of the nail beds. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral, but not central, cyanosis. Pseudocyanosis is a bluish or slate-gray skin discoloration due to drugs (chlorpromazine, minocycline, amiodarone, nicorandil) or heavy metals (gold, silver). 55,56 In pseudocyanosis, the lips and mucous mem branes are of normal color, the abnormal skin discoloration does not blanch with pressure, and the discoloration tends to be more intense in sun-exposed areas. Focal areas of pseudocyanosis may be due to local contact with color dyes, gold, or silver. DIAGNOSIS AND TREATMENT Pulse oximetry can detect hypoxemia and provide an accurate oxygen saturation measurement. However, with hemoglobinopathies, standard pulse oximetry is often inaccurate. In methemoglobinemia, pulse oximetry will read 80% to 85% regardless of the oxygen level, potentially overestimating the true oxygen saturation (it may be lower, but pulse oximetry will not read lower). With carboxyhemoglobinemia, the pulse oximetry reads carboxyhemoglobin as oxyhemoglobin, reporting a higher percentage for oxygen saturation (see Chapter 207, “Dyshemoglobinemias, ” and Chapter 222, “Carbon Monoxide”). Arterial blood gas analysis using co-oximetry (a specific multiwavelength measure ment of oxygen saturation) accurately detects oxygenation in those with cyanosis. In central cyanosis, the oxygen saturation measured from the arterial blood gas is lower because of the underlying hypoxemia. In peripheral cyanosis, the oxygen saturation should be normal.

co-oximetry (a specific multiwavelength measure ment of oxygen saturation) accurately detects oxygenation in those with cyanosis. In central cyanosis, the oxygen saturation measured from the arterial blood gas is lower because of the underlying hypoxemia. In peripheral cyanosis, the oxygen saturation should be normal. With methemoglobinemia or carboxyhemoglobinemia, arterial blood gas co-oximetry will show a normal Pa o 2 (reflecting a normal amount of dissolved oxygen in the plasma), a normal calculated oxygen saturation (from the normal Pa o 2), and a decreased measured oxygen saturation (because of a decreased number of oxygen-binding sites). Administer oxygen to all patients with central cyanosis; failure to improve suggests impaired circulation (shock), abnormal hemoglobin, or pseudocyanosis.  PLEURAL EFFUSION INTRODUCTION Pleural effusions result from fluid accumulating in the potential space between the visceral and parietal pleurae. 57 Although pleural effusions can result from many causes, in developed countries, the most com mon causes are heart failure, pneumonia, and cancer, with tuberculosis a common cause in the developing world ( Table 62-10). 57-60 Multiple causes may be common, as seen in 30% of patients with a unilateral pleural effusion in a single study. Continuously secreted fluid from the parietal pleura into the pleural space is absorbed by the visceral pleural microcirculation, averaging about 8 L/d in an adult. This fluid reduces friction between the pleural layers and allows for smooth lung expansion and contraction with res piration. Any process that increases fluid production or interferes with fluid absorption will result in accumulation in the pleural space. Pleural effusions are traditionally divided into exudates or transudates. 57,60 TABLE 62-8 Differential Diagnosis of Cyanosis Central Cyanosis Peripheral Cyanosis Hypoxemia Decreased fraction of inspired oxygen: high altitude Hypoventilation Ventilation–perfusion mismatch Right-to-left shunt: congenital heart disease, pulmonary arteriovenous fistulas, multiple intrapulmonary shunts Reduced cardiac output Cold extremities Maldistribution of blood flow: distributive forms of shock Arterial or venous obstruction Abnormal hemoglobin Methemoglobinemia: hereditary, acquired Sulfhemoglobinemia: acquired Carboxyhemoglobinemia TABLE 62-9 Factors Influencing the Physical Appearance of Cyanosis Physiologic factors •   Oxygen content of blood •   Degree of oxygen extraction •   Oxyhemoglobin dissociation curve Anatomic factors •   Status of microcirculation •   Skin pigmentation •   Skin thickness Physical factors •   Quality/intensity of light in examination area •   Skill of examining physician TABLE 62-7 Treatment of Hiccups: Drug Treatment Drug Initial Dose in ED Maintenance Dose on Discharge Chlorpromazine 25–50 milligrams IV; repeat in 2–4 h if needed 25–50 milligrams PO 3–4 times a day Metoclopramide* 10 milligrams IV or IM 10–20 milligrams PO 3 times a day for 10 d Haloperidol * 2–5 milligrams IM 2–4 milligrams PO 3 times a day Nifedipine* 10–20 milligrams PO 10–20 milligrams PO 3–4 to times a day Valproic acid* 15 milligrams/kg PO 15 milligrams/kg PO 3 times a day Baclofen* 10 milligrams PO 10 milligrams PO 3 times a day, titrated up to 75 milligrams per day Gabapentin * 100 milligrams 100 milligrams PO 3 times a day, titrated up to 120 milligrams per day *Not approved by the U.S. Food and Drug Administration for treatment of hiccups. Tintinalli_Sec08_p0425-0472.indd 430 8/1/19 2:10 PM

n* 10 milligrams PO 10 milligrams PO 3 times a day, titrated up to 75 milligrams per day Gabapentin * 100 milligrams 100 milligrams PO 3 times a day, titrated up to 120 milligrams per day *Not approved by the U.S. Food and Drug Administration for treatment of hiccups. Tintinalli_Sec08_p0425-0472.indd 430 8/1/19 2:10 PM CHAPTER 62: Respiratory Distress 431 Exudative effusions result from pleural disease, usually inflammation or neoplasia that produces active fluid secretion or leakage with high pro tein content. Transudative effusions result from an imbalance between hydrostatic and oncotic pressures. This imbalance results in the production of an ultrafiltrate with low protein content into the pleural space. CLINICAL FEATURES A pleural effusion may be clinically silent or come to detection as a result of symptoms of an underlying disease, an increase in volume of the effusion causing dyspnea, or the development of inflammation and associ ated pain with respiration. Physical findings of a pleural effusion include percussion dullness and decreased breath sounds. Because pleural fluid typically pools in the dependent portions of the hemithorax, small or moderate-size effusions have percussion dullness and decreased breath sounds at the lung base with relatively normal lung findings above the level of fluid. With large or massive effusions, it may be impossible to distinguish a fluid level on clinical examination. DIAGNOSIS In an adult, at least 150 to 200 mL of pleural fluid in the hemithorax exists if seen on upright chest radiography. Supine chest radiographs may demonstrate only a hazy appearance of pleural fluid from layering in the posterior pleural space ( Figure 62-1A). US detects pleural fluid at the bedside. CT scans of the chest may clarify uncertain findings on chest radiograph ( Figure 62-1B). Small free-flowing pleural effusions are better visualized on decubitus radiographic views ( Figure 62-2). US can also identify a pleural effusion. A significant pleural effusion is large enough to produce a pleural fluid strip >10 mm wide on lateral decubitus radiographic views or by US. Diagnostic thoracentesis obtains pleural fluid for analysis in cases without a clearly evident cause, to confirm a suspected diagnosis, or to detect pleural space infection. Diagnostic thoracentesis is not initially necessary if the cause is likely heart failure based on a typical clinical appearance; a period of treatment with monitoring for pleural fluid resolution can be initiated with thoracentesis reserved for patients who do not experience resolution in 3 to 4 days. The Light criteria are widely used to differentiate transudates from exudates using serum and pleural fluid protein and lactate dehydrogenase levels (Table 62-11). 62 The overall sensitivity of the Light criteria to identify exudative pleural effusion is 98% to 99%, with specificity from 65% to 86%. 77,60,62 Standard tests for pleural fluid analysis should include protein and lactate dehydrogenase levels (Table 62-11). The distinction between exudates and transudates may be obscured by the effect of diuretic therapy in patients with transudative pleural effusions. During diuresis, the resorption of water is faster than that of protein, so the protein concentration rises into the range consistent with an exudative etiology. A serum to pleural albumin difference of >1.2 grams/dL (12 grams/L) may help in this scenario, but this approach will reduce the sensitivity of exudative pleural effusion detection by >10%. TREATMENT Therapeutic thoracentesis with drainage of 1.0 to 1.5 L of fluid is indicated if the patient has dyspnea at rest. Acute drainage of larger volumes is associated with reexpansion pulmonary edema, so largevolume drainage is to be avoided.

l reduce the sensitivity of exudative pleural effusion detection by >10%. TREATMENT Therapeutic thoracentesis with drainage of 1.0 to 1.5 L of fluid is indicated if the patient has dyspnea at rest. Acute drainage of larger volumes is associated with reexpansion pulmonary edema, so largevolume drainage is to be avoided. Optimization of medical therapy typically resolves >80% of effusions due to heart failure within 2 weeks. 63,64 TABLE 62-10 Differential Diagnosis of Pleural Effusion Common Less Common Transudates Heart failure Cirrhosis with ascites Peritoneal dialysis Nephrotic syndrome Exudates Cancer: primary or metastatic Viral, fungal, mycobacterial, or parasitic infection Bacterial pneumonia with parapneumonic effusion Systemic rheumatologic disorders: systemic lupus erythematosus, rheumatoid arthritis Pulmonary embolism Uremia, pancreatitis Postcardiac surgery or radiotherapy Drug related: amiodarone Inconclusive; features of both transudate and exudate Transudates after diuretic therapy Pulmonary embolism FIGURE 62-1. A. Supine radiograph showing a right-sided pleural effusion. The right lung field is hazy compared to the left, and a small layer of fluid is noted inferiorly. B. CT scan of the same patient. A moderate pleural effusion is seen in the right lung field, and a small effusion not seen in the left lung field of the plain radiograph is present on the CT scan. Tintinalli_Sec08_p0425-0472.indd 431 8/1/19 2:10 PM