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InternalMed_Harrison. The cough of chronic bronchitis in long-term cigarette smokers rarely leads the patient to seek medical advice. It lasts for only seconds to a CAuSES of iMPAiRED CougH


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InternalMed_Harrison. Central respiratory depression (e.g., anesthesia, sedation, or coma) 244 few minutes, is productive of benign-appearing mucoid sputum, and generally does not cause discomfort. Cough may occur in the context of other respiratory symptoms that together point to a diagnosis; for example, cough accompanied by wheezing, shortness of breath, and chest tightness after exposure to a cat or other sources of allergens suggests asthma. At times, however, cough is the dominant or sole symptom of disease, and it may be of sufficient duration and severity that relief is sought. The duration of cough is a clue to its etiology. Acute cough (<3 weeks) is most commonly due to a respiratory tract infection, aspiration, or inhalation of noxious chemicals or smoke. Subacute cough (3–8 weeks in duration) is a common residuum of tracheobronchitis, as in pertussis or “postviral tussive syndrome.” Chronic cough (>8 weeks) may be caused by a wide variety of cardiopulmonary diseases, including those of


InternalMed_Harrison

InternalMed_Harrison. is a common residuum of tracheobronchitis, as in pertussis or “postviral tussive syndrome.” Chronic cough (>8 weeks) may be caused by a wide variety of cardiopulmonary diseases, including those of inflammatory, infectious, neoplastic, and cardiovascular etiologies. When initial assessment with chest examination and radiography is normal, cough-variant asthma, gastroesophageal reflux, nasopharyngeal drainage, and medications (angiotensin-converting enzyme [ACE] inhibitors) are the most common causes of chronic cough.


InternalMed_Harrison

InternalMed_Harrison. Details as to the sound, the time of occurrence during the day, and the pattern of coughing infrequently provide useful etiologic clues. Regardless of cause, cough often worsens upon first lying down at night, with talking, or with the hyperpnea of exercise; it frequently improves with sleep. An exception may involve the cough that occurs only with certain allergic exposures or exercise in cold air, as in asthma. Useful historical questions include what circumstances surround the onset of cough, what makes the cough better or worse, and whether or not the cough produces sputum.


InternalMed_Harrison

InternalMed_Harrison. The physical examination seeks clues suggesting the presence of cardiopulmonary disease, including findings such as wheezing or crackles on chest examination. Examination of the auditory canals and tympanic membranes (for irritation of the latter resulting in stimulation of Arnold’s nerve), the nasal passageways (for rhinitis or polyps), and the nails (for clubbing) may also provide etiologic clues. Because cough can be a manifestation of a systemic disease such as sarcoidosis or vasculitis, a thorough general examination is equally important.


InternalMed_Harrison

InternalMed_Harrison. In virtually all instances, evaluation of chronic cough merits a chest radiograph. The list of diseases that can cause persistent cough without other symptoms and without detectable abnormalities on physical examination is long. It includes serious illnesses such as sarcoidosis or Hodgkin’s disease in young adults, lung cancer in older patients, and (worldwide) pulmonary tuberculosis. An abnormal chest film prompts an evaluation aimed at explaining the cough. In a patient with chronic productive cough, examination of expectorated sputum is warranted. Purulent-appearing sputum should be sent for routine bacterial culture and, in certain circumstances, mycobacterial culture as well. Cytologic examination of mucoid sputum may be useful to assess for malignancy and to distinguish neutrophilic from eosinophilic bronchitis. Expectoration of blood—whether streaks of blood, blood mixed with airway secretions, or pure blood—deserves a special approach to assessment and management (see


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InternalMed_Harrison. from eosinophilic bronchitis. Expectoration of blood—whether streaks of blood, blood mixed with airway secretions, or pure blood—deserves a special approach to assessment and management (see “Hemoptysis,” below).


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InternalMed_Harrison. It is commonly held that (alone or in combination) the use of an ACE inhibitor; postnasal drainage; gastroesophageal reflux; and asthma account for more than 90% of cases of chronic cough with a normal or noncontributory chest radiograph. However, clinical experience does not support this contention, and strict adherence to this concept discourages the search for alternative explanations by both clinicians and researchers. ACE inhibitor–induced cough occurs in 5–30% of patients taking these agents and is not dose dependent. ACE metabolizes bradykinin and other tachykinins, such as substance P. The mechanism of ACE inhibitor–associated cough may involve sensitization of sensory nerve endings due to accumulation of bradykinin. In support of this hypothesis, polymorphisms in the neurokinin-2 receptor gene are associated with ACE inhibitor–induced cough. Any patient with


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases chronic unexplained cough who is taking an ACE inhibitor should have a trial period off the medication, regardless of the timing of the onset of cough relative to the initiation of ACE inhibitor therapy. In most instances, a safe alternative is available; angiotensin-receptor blockers do not cause cough. Failure to observe a decrease in cough after 1 month off medication argues strongly against this etiology. Postnasal drainage of any etiology can cause cough as a response to stimulation of sensory receptors of the cough-reflex pathway in the hypopharynx or aspiration of draining secretions into the trachea. Clues suggesting this etiology include postnasal drip, frequent throat clearing, and sneezing and rhinorrhea. On speculum examination of the nose, excess mucoid or purulent secretions, inflamed and edematous nasal mucosa, and/or polyps may be seen; in addition, secretions or a cobblestoned appearance of the mucosa along


InternalMed_Harrison

InternalMed_Harrison. examination of the nose, excess mucoid or purulent secretions, inflamed and edematous nasal mucosa, and/or polyps may be seen; in addition, secretions or a cobblestoned appearance of the mucosa along the posterior pharyngeal wall may be noted. Unfortunately, there is no means by which to quantitate postnasal drainage. In many instances, this diagnosis must rely on subjective information provided by the patient. This assessment must also be counterbalanced by the fact that many people who have chronic postnasal drainage do not experience cough.


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InternalMed_Harrison. Linking gastroesophageal reflux to chronic cough poses similar challenges. It is thought that reflux of gastric contents into the lower esophagus may trigger cough via reflex pathways initiated in the esophageal mucosa. Reflux to the level of the pharynx (laryngopharyngeal reflux), with consequent aspiration of gastric contents, causes a chemical bronchitis and possibly pneumonitis that can elicit cough for days afterward. Retrosternal burning after meals or on recumbency, frequent eructation, hoarseness, and throat pain may be indicative of gastroesophageal reflux. Nevertheless, reflux may also elicit minimal or no symptoms. Glottic inflammation detected on laryngoscopy may be a manifestation of recurrent reflux to the level of the throat, but it is a nonspecific finding. Quantification of the frequency and level of reflux requires a somewhat invasive procedure to measure esophageal pH directly (either nasopharyngeal placement of a catheter with a pH probe into the esophagus for 24 h


InternalMed_Harrison

InternalMed_Harrison. the frequency and level of reflux requires a somewhat invasive procedure to measure esophageal pH directly (either nasopharyngeal placement of a catheter with a pH probe into the esophagus for 24 h or endoscopic placement of a radio-transmitter capsule into the esophagus). The precise interpretation of test results that permits an etiologic linking of reflux events and cough remains debated. Again, assigning the cause of cough to gastroesophageal reflux must be weighed against the observation that many people with symptomatic reflux do not experience chronic cough.


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InternalMed_Harrison. Cough alone as a manifestation of asthma is common among children but not among adults. Cough due to asthma in the absence of wheezing, shortness of breath, and chest tightness is referred to as “cough-variant asthma.” A history suggestive of cough-variant asthma ties the onset of cough to exposure to typical triggers for asthma and the resolution of cough to discontinuation of exposure. Objective testing can establish the diagnosis of asthma (airflow obstruction on spirometry that varies over time or reverses in response to a bronchodilator) or exclude it with certainty (a negative response to a bronchoprovocation challenge—e.g., with methacholine). In a patient capable of taking reliable measurements, home expiratory peak flow monitoring can be a cost-effective method to support or discount a diagnosis of asthma.


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InternalMed_Harrison. Chronic eosinophilic bronchitis causes chronic cough with a normal chest radiograph. This condition is characterized by sputum eosinophilia in excess of 3% without airflow obstruction or bronchial hyperresponsiveness and is successfully treated with inhaled glucocorticoids.


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InternalMed_Harrison. Treatment of chronic cough in a patient with a normal chest radio-graph is often empirical and is targeted at the most likely cause(s) of cough as determined by history, physical examination, and possibly pulmonary-function testing. Therapy for postnasal drainage depends on the presumed etiology (infection, allergy, or vasomotor rhinitis) and may include systemic antihistamines; antibiotics; nasal saline irrigation; and nasal pump sprays with glucocorticoids, antihistamines, or anticholinergics. Antacids, histamine type 2 (H2) receptor antagonists, and proton-pump inhibitors are used to neutralize or decrease the production of gastric acid in gastroesophageal reflux disease; dietary changes, elevation of the head and torso during sleep, and medications to improve gastric emptying are additional therapeutic measures. Cough-variant asthma typically responds well to inhaled glucocorticoids and intermittent use of inhaled β-agonist bronchodilators.


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InternalMed_Harrison. Cough-variant asthma typically responds well to inhaled glucocorticoids and intermittent use of inhaled β-agonist bronchodilators. Patients who fail to respond to treatment targeting the common causes of chronic cough or who have had these causes excluded by appropriate diagnostic testing should undergo chest CT. Diseases causing cough that may be missed on chest x-ray include tumors, early interstitial lung disease, bronchiectasis, and atypical mycobacterial pulmonary infection. On the other hand, patients with chronic cough who have normal findings on chest examination, lung function testing, oxygenation assessment, and chest CT can be reassured as to the absence of serious pulmonary pathology.


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InternalMed_Harrison. Chronic idiopathic cough, also called cough hypersensitivity syndrome, is distressingly common. It is often experienced as a tickle or sensitivity in the throat, occurs more often in women, and is typically “dry” or at most productive of scant amounts of mucoid sputum. It can be exhausting, interfere with work, and cause social embarrassment. Once serious underlying cardiopulmonary pathology has been excluded, an attempt at cough suppression is appropriate. Most effective are narcotic cough suppressants, such as codeine or hydrocodone, which are thought to act in the “cough center” in the brainstem. The tendency of narcotic cough suppressants to cause drowsiness and constipation and their potential for addictive dependence limit their appeal for longterm use. Dextromethorphan is an over-the-counter, centrally acting cough suppressant with fewer side effects and less efficacy than the narcotic cough suppressants. Dextromethorphan is thought to have a different site of action than


InternalMed_Harrison

InternalMed_Harrison. centrally acting cough suppressant with fewer side effects and less efficacy than the narcotic cough suppressants. Dextromethorphan is thought to have a different site of action than narcotic cough suppressants and can be used in combination with them if necessary. Benzonatate is thought to inhibit neural activity of sensory nerves in the cough-reflex pathway. It is generally free of side effects; however, its effectiveness in suppressing cough is variable and unpredictable. Case series have reported benefit from off-label use of gabapentin or amitriptyline for chronic idiopathic cough. Novel cough suppressants without the limitations of currently available agents are greatly needed. Approaches that are being explored include the development of neurokinin receptor antagonists, type 1 vanilloid receptor antagonists, and novel opioid and opioid-like receptor agonists.


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InternalMed_Harrison. Hemoptysis, the expectoration of blood from the respiratory tract, can arise at any location from the alveoli to the glottis. It is important to distinguish hemoptysis from epistaxis (bleeding from the nasopharynx) and hematemesis (bleeding from the upper gastrointestinal tract). Hemoptysis can range from the expectoration of blood-tinged sputum to that of life-threatening large volumes of bright red blood. For most patients, any degree of hemoptysis can cause anxiety and often prompts medical evaluation.


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InternalMed_Harrison. While precise epidemiologic data are lacking, the most common etiology of hemoptysis is infection of the medium-sized airways. In the United States, the cause is usually viral or bacterial bronchitis. Hemoptysis can arise in the setting of acute bronchitis or during an exacerbation of chronic bronchitis. Worldwide, the most common cause of hemoptysis is infection with Mycobacterium tuberculosis, presumably because of the high prevalence of tuberculosis and its predilection for cavity formation. While these are the most common causes, the differential diagnosis for hemoptysis is extensive, and a step-wise approach to evaluation is appropriate.


InternalMed_Harrison

InternalMed_Harrison. One way to approach the source of hemoptysis is to search systematically for potential sites of bleeding from the alveolus to the mouth. Diffuse bleeding in the alveolar space, often referred to as diffuse alveolar hemorrhage (DAH), may present as hemoptysis. Causes of DAH can be inflammatory or noninflammatory. Inflammatory DAH is due to small-vessel vasculitis/capillaritis from a variety of diseases, including granulomatosis with polyangiitis and microscopic polyangiitis. Similarly, systemic autoimmune diseases such as systemic lupus erythematosus 245 can manifest as pulmonary capillaritis. Antibodies to the alveolar basement membrane, as are seen in Goodpasture’s disease, can also result in alveolar hemorrhage. In the early period after bone marrow transplantation, patients can develop a form of inflammatory DAH that can be catastrophic and life-threatening. The exact pathophysiology of this process is not well understood, but DAH should be suspected in patients with sudden-onset


InternalMed_Harrison

InternalMed_Harrison. a form of inflammatory DAH that can be catastrophic and life-threatening. The exact pathophysiology of this process is not well understood, but DAH should be suspected in patients with sudden-onset dyspnea and hypoxemia in the first 100 days after bone marrow transplantation.


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InternalMed_Harrison. Alveoli can also bleed due to direct inhalational injury, including thermal injury from fires, inhalation of illicit substances (e.g., cocaine), and inhalation of toxic chemicals. If alveoli are irritated from any process, patients with thrombocytopenia, coagulopathy, or antiplatelet or anticoagulant use will be at increased risk of hemoptysis.


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InternalMed_Harrison. Bleeding in hemoptysis most commonly arises from the smallto medium-sized airways. Irritation and injury of the bronchial mucosa can lead to small-volume bleeding. More significant hemoptysis can result from the proximity of the bronchial artery and vein to the airway, with these vessels and the bronchus running together in what is often referred to as the bronchovascular bundle. In the smaller airways, these blood vessels are close to the airspace, and lesser degrees of inflammation or injury can therefore result in their rupture into the airways. While alveolar hemorrhage arises from capillaries that are part of the low-pressure pulmonary circulation, bronchial bleeding generally originates from bronchial arteries, which are under systemic pressure and thus are predisposed to larger-volume bleeding.


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InternalMed_Harrison. Any infection of the airways can result in hemoptysis, although acute bronchitis is most commonly caused by viral infection. In patients with a history of chronic bronchitis, bacterial superinfection with organisms such as Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis can also result in hemoptysis. Patients with bronchiectasis (a permanent dilation of the airways with loss of mucosal integrity) are particularly prone to hemoptysis due to chronic inflammation and anatomic abnormalities that bring the bronchial arteries closer to the mucosal surface. One common presentation of patients with advanced cystic fibrosis—the prototypical bronchiectatic lung disease—is hemoptysis, which can be life-threatening.


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InternalMed_Harrison. Pneumonias of any sort can cause hemoptysis. Tuberculous infection, which can lead to bronchiectasis or cavitary pneumonia, is a very common cause of hemoptysis worldwide. Patients may present with a chronic cough productive of blood-streaked sputum or with larger-volume bleeding. Rasmussen’s aneurysm (the dilation of a pulmonary artery in a cavity formed by previous tuberculous infection) remains a source of massive, life-threatening hemoptysis in the developing world. Community-acquired pneumonia and lung abscess can also result in bleeding. Once again, if the infection results in cavitation, there is a greater likelihood of bleeding due to erosion into blood vessels. Infections with Staphylococcus aureus and gram-negative rods (e.g., Klebsiella pneumoniae) are especially likely to cause necrotizing lung infections and thus to be associated with hemoptysis.


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InternalMed_Harrison. While not common in North America, pulmonary paragoni miasis (i.e., infection with the lung fluke Paragonimus wester mani) often presents as fever, cough, and hemoptysis. This infection is a public health issue in Southeast Asia and China and is frequently confused with active tuberculosis, in which the clinical picture can be similar. Paragonimiasis should be considered in recent immigrants from endemic areas who have new or recurrent hemoptysis. In addition, pulmonary paragonimiasis has been reported secondary to ingestion of crayfish or small crabs in the United States. Other causes of airway irritation resulting in hemoptysis include inhalation of toxic chemicals, thermal injury, and direct trauma from suctioning of the airways (particularly in intubated patients). All of these etiologies should be considered in light of the individual patient’s history and exposures.


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InternalMed_Harrison. Perhaps the most feared cause of hemoptysis is bronchogenic lung cancer, although hemoptysis is a presenting symptom in only ∼10% of patients. Cancers arising in the proximal airways are much more likely to cause hemoptysis, but any malignancy in the chest can do so. Because both squamous cell carcinomas and small-cell carcinomas are 246 more commonly in or adjacent to the proximal airways, and large at presentation, they are more often a cause of hemoptysis. These cancers can present with large-volume and life-threatening hemoptysis because of erosion into the hilar vessels. Carcinoid tumors, which are found almost exclusively as endobronchial lesions with friable mucosa, can also present with hemoptysis. In addition to cancers arising in the lung, metastatic disease in the pulmonary parenchyma can bleed. Malignancies that commonly metastasize to the lungs include renal cell, breast, colon, testicular, and thyroid cancers as well as melanoma. While hemoptysis is not a common


InternalMed_Harrison

InternalMed_Harrison. parenchyma can bleed. Malignancies that commonly metastasize to the lungs include renal cell, breast, colon, testicular, and thyroid cancers as well as melanoma. While hemoptysis is not a common manifestation of pulmonary metastases, the combination of multiple pulmonary nodules and hemoptysis should raise suspicion of this etiology. Finally, disease of the pulmonary vasculature can cause hemoptysis. Perhaps most frequently, congestive heart failure with transmission of elevated left atrial pressures can lead to rupture of small alveolar capillaries. These patients rarely present with bright red blood but more commonly have pink, frothy sputum or blood-tinged secretions. Patients with a focal jet of mitral regurgitation can present with an upper-lobe opacity on chest radiography together with hemoptysis. This finding is thought to be due to focal increases in pulmonary capillary pressure due to the regurgitant jet. Pulmonary arteriovenous malformations are prone to bleeding. Pulmonary


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InternalMed_Harrison. hemoptysis. This finding is thought to be due to focal increases in pulmonary capillary pressure due to the regurgitant jet. Pulmonary arteriovenous malformations are prone to bleeding. Pulmonary embolism can also lead to the development of hemoptysis, which is generally associated with pulmonary infarction. Pulmonary arterial hypertension from other causes rarely results in hemoptysis.


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InternalMed_Harrison. As with most signs of possible illness, the initial step in the evaluation of hemoptysis is a thorough history and physical examination (Fig. 48-2). As already mentioned, initial questioning should focus on ascertaining whether the bleeding is truly from the respiratory tract and not the nasopharynx or gastrointestinal tract; bleeding from the latter sources requires different approaches to evaluation and treatment. History and Physical Examination The specific characteristics of hemoptysis may be helpful in determining an etiology, such as whether the expectorated material consists of blood-tinged, purulent secretions; pink, frothy sputum; or pure blood. Information on specific triggers


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases of the bleeding (e.g., recent inhalation exposures) as well as any previous episodes of hemoptysis should be elicited during history-taking. Monthly hemoptysis in a woman suggests catamenial hemoptysis from pulmonary endometriosis. Moreover, the volume of blood expectorated is important not only in determining the cause but also in gauging the urgency for further diagnostic and therapeutic maneuvers. Patients rarely exsanguinate from hemoptysis but can effectively “drown” in aspirated blood. Large-volume hemoptysis, referred to as massive hemoptysis, is variably defined as hemoptysis of >200–600 mL in 24 h. Massive hemoptysis should be considered a medical emergency. All patients should be asked about current or former cigarette smoking; this behavior predisposes to chronic bronchitis and increases the likelihood of bronchogenic cancer. Practitioners should inquire about symptoms and signs suggestive of respiratory tract


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InternalMed_Harrison. smoking; this behavior predisposes to chronic bronchitis and increases the likelihood of bronchogenic cancer. Practitioners should inquire about symptoms and signs suggestive of respiratory tract infection (including fever, chills, and dyspnea), recent inhalation exposures, recent use of illicit substances, and risk factors for venous thromboembolism.


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InternalMed_Harrison. A medical history of malignancy or treatment thereof, rheumatologic disease, vascular disease, or underlying lung disease (e.g., bronchiectasis) may be relevant to the cause of hemoptysis. Because many causes of DAH can be part of a pulmonary-renal syndrome, specific inquiry into a history of renal insufficiency is important.


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InternalMed_Harrison. The physical examination begins with an assessment of vital signs and oxygen saturation to gauge whether there is evidence of life-threatening bleeding. Tachycardia, hypotension, and decreased oxygen saturation mandate a more expedited evaluation of hemoptysis. A specific focus on respiratory and cardiac examinations is important; these examinations should include inspection of the nares, auscultation of the lungs and heart, assessment of the lower extremities for symmetric or asymmetric edema, and evaluation for jugular venous distention. Clubbing of the digits may suggest underlying lung diseases such as bronchogenic carcinoma or bronchiectasis, which predispose to hemoptysis. Similarly, mucocutaneous telangiectasias should raise the specter of pulmonary arterial-venous malformations.


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InternalMed_Harrison. Diagnostic Evaluation For most patients, the next step in evaluation of hemoptysis should be a standard chest radiograph. If a source of bleeding is not identified on plain film, CT of the chest should be performed. CT allows better delineation of bronchiectasis, alveolar filling, cavitary infiltrates, and masses than does chest radiograph. The practitioner should consider a CT protocol to assess for pulmonary embolism if the history or examination suggests venous thromboembolism as a cause of bleeding.


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InternalMed_Harrison. Quantify amount of bleeding History and physical exam Patient with hemoptysis Mild Moderate Massive Rule out other sources: • Oropharynx • Gastrointestinal tract No risk factors* Risk factors* or recurrent bleeding Treat underlying disease (usually infection) CT scan if unrevealing, bronchoscopy Bleeding continues Treat underlying disease CT scan Bronchoscopy CXR, CBC, coagulation studies, UA, creatinine Secure airway Treat underlying disease Persistent bleeding *Risk Factors: smoking, age >40 Bleeding stops Embolization or resection FIguRE 48-2 Decision tree for evaluation of hemoptysis. CBC, complete blood count; CT, computed tomography; CXR, chest x-ray; UA, urinalysis.


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InternalMed_Harrison. Laboratory studies should include a complete blood count to assess both the hematocrit and the platelet count as well as coagulation studies. Renal function should be evaluated and urinalysis conducted because of the possibility of pulmonary-renal syndromes presenting with hemoptysis. The documentation of acute renal insufficiency or the detection of red blood cells or their casts on urinalysis should elevate suspicion of small-vessel vasculitis, and studies such as antineutrophil cytoplasmic antibody, antiglomerular basement membrane antibody, and antinuclear antibody should be considered. If a patient is producing sputum, Gram’s and acid-fast staining as well as culture should be undertaken. If all of these studies are unrevealing, bronchoscopy should be considered. In any patient with a history of cigarette smoking, airway inspection should be part of the evaluation of new-onset hemoptysis as endobronchial lesions are not reliably visualized on CT.


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InternalMed_Harrison. For the most part, the treatment of hemoptysis varies with its etiology. However, large-volume, life-threatening hemoptysis generally requires immediate intervention regardless of the cause. The first step is to establish a patent airway, usually by endotracheal intubation and subsequent mechanical ventilation. As large-volume hemoptysis usually arises from an airway lesion, it is ideal to identify the site of bleeding by either chest imaging or bronchoscopy (more commonly rigid rather than flexible). The goals are then to isolate the bleeding to one lung and not to allow the preserved airspaces in the other lung to be filled with blood so that gas exchange is further impaired. Patients should be placed with the bleeding lung in a dependent position (i.e., bleeding-side down), and, if possible, dual-lumen endotracheal tubes or an airway blocker should be placed in the proximal airway of the bleeding lung. These interventions generally require the assistance of anesthesiologists,


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InternalMed_Harrison. possible, dual-lumen endotracheal tubes or an airway blocker should be placed in the proximal airway of the bleeding lung. These interventions generally require the assistance of anesthesiologists, interventional pulmonologists, or thoracic surgeons.


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InternalMed_Harrison. If the bleeding does not stop with treatment of the underlying cause and the passage of time, severe hemoptysis from bronchial arteries can be treated with angiographic embolization of the responsible bronchial artery. This intervention should be entertained only in the most severe and life-threatening cases of hemoptysis because of the risk of unintentional spinal-artery embolization and consequent paraplegia. Endobronchial lesions can be treated with a variety of bronchoscopically directed interventions, including cauterization and laser therapy. In extreme circumstances, surgical resection of the affected region of the lung is considered. Most cases of hemoptysis resolve with treatment of the infection or inflammatory process or with removal of the offending stimulus.


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InternalMed_Harrison. products from them. Proper maintenance of this function depends not only on intact cardiovascular and respiratory systems, but also on an adequate number of red blood cells and hemoglobin and a supply of inspired gas containing adequate O2. Decreased O2 availability to cells results in an inhibition of oxidative phosphorylation and increased anaerobic glycolysis. This switch from aerobic to anaerobic metabolism, the Pasteur effect, maintains some, albeit reduced, adenosine 5′-triphosphate (ATP) production. In severe hypoxia, when ATP production is inadequate to meet the energy requirements of ionic and osmotic equilibrium, cell membrane depolarization leads to uncontrolled Ca2+ influx and activation of Ca2+-dependent phospholipases and proteases. These events, in turn, cause cell swelling, activation of apoptotic pathways, and, ultimately, cell death.


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InternalMed_Harrison. The adaptations to hypoxia are mediated, in part, by the upregulation of genes encoding a variety of proteins, including glycolytic enzymes, such as phosphoglycerate kinase and phosphofructokinase, as well as the glucose transporters Glut-1 and Glut-2; and by growth factors, such as vascular endothelial growth factor (VEGF) and erythropoietin, which enhance erythrocyte production. The hypoxia-induced increase in expression of these key proteins is governed by the hypoxia-sensitive transcription factor, hypoxia-inducible factor-1 (HIF-1).


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InternalMed_Harrison. During hypoxia, systemic arterioles dilate, at least in part, by opening of KATP channels in vascular smooth-muscle cells due to the hypoxia-induced reduction in ATP concentration. By contrast, in pulmonary vascular smooth-muscle cells, inhibition of K+ channels causes depolarization which, in turn, activates voltage-gated Ca2+ channels raising the cytosolic [Ca2+] and causing smooth-muscle cell contraction. Hypoxia-induced pulmonary arterial constriction shunts blood away from poorly ventilated portions toward better ventilated portions of the lung; however, it also increases pulmonary vascular resistance and right ventricular afterload.


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InternalMed_Harrison. Effects on the Central Nervous System Changes in the central nervous system (CNS), particularly the higher centers, are especially important consequences of hypoxia. Acute hypoxia causes impaired judgment, motor incoordination, and a clinical picture resembling acute alcohol intoxication. High-altitude illness is characterized by headache secondary to cerebral vasodilation, gastrointestinal symptoms, dizziness, insomnia, fatigue, or somnolence. Pulmonary arterial and sometimes venous constriction causes capillary leakage and high-altitude pulmonary edema (HAPE) (Chap. 47e), which intensifies hypoxia, further promoting vasoconstriction. Rarely, high-altitude cerebral edema (HACE) develops, which is manifest by severe headache and papilledema and can cause coma. As hypoxia becomes more severe, the regulatory centers of the brainstem are affected, and death usually results from respiratory failure.


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InternalMed_Harrison. Effects on the Cardiovascular System Acute hypoxia stimulates the chemoreceptor reflex arc to induce venoconstriction and systemic arterial vasodilation. These acute changes are accompanied by transiently increased myocardial contractility, which is followed by depressed myocardial contractility with prolonged hypoxia.


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InternalMed_Harrison. CAuSES OF HYPOXIA Respiratory Hypoxia When hypoxia occurs from respiratory failure, Pao2 declines, and when respiratory failure is persistent, the hemoglobin-oxygen (Hb-O2) dissociation curve (see Fig. 127-2) is displaced to the right, with greater quantities of O2 released at any level of tissue Po2. Arterial hypoxemia, i.e., a reduction of O2 saturation of arterial blood (Sao2), and consequent cyanosis are likely to be more marked when such depression of Pao2 results from pulmonary disease than when the depression occurs as the result of a decline in the fraction of oxygen in inspired air (Fio2). In this latter situation, Paco2 falls secondary to anoxia-induced hyperventilation and the Hb-O2 dissociation curve is displaced to the left, limiting the decline in Sao2 at any level of Pao2.


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InternalMed_Harrison. The most common cause of respiratory hypoxia is ventilation-perfusion mismatch resulting from perfusion of poorly ventilated alveoli. Respiratory hypoxemia may also be caused by hypoventilation, in which case it is associated with an elevation of Paco2 (Chap. 306e). These two forms of respiratory hypoxia are usually correctable by 248 inspiring 100% O2 for several minutes. A third cause of respiratory hypoxia is shunting of blood across the lung from the pulmonary arterial to the venous bed (intrapulmonary right-to-left shunting) by perfusion of nonventilated portions of the lung, as in pulmonary atelectasis or through pulmonary arteriovenous connections. The low Pao2 in this situation is only partially corrected by an Fio2 of 100%.


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InternalMed_Harrison. Hypoxia Secondary to High Altitude As one ascends rapidly to 3000 m (~10,000 ft), the reduction of the O2 content of inspired air (Fio2) leads to a decrease in alveolar Po2 to approximately 60 mmHg, and a condition termed high-altitude illness develops (see above). At higher altitudes, arterial saturation declines rapidly and symptoms become more serious; and at 5000 m, unacclimated individuals usually cease to be able to function normally owing to the changes in CNS function described above. Hypoxia Secondary to Right-to-Left Extrapulmonary Shunting From a physiologic viewpoint, this cause of hypoxia resembles intrapulmonary right-to-left shunting but is caused by congenital cardiac malformations, such as tetralogy of Fallot, transposition of the great arteries, and Eisenmenger’s syndrome (Chap. 282). As in pulmonary right-toleft shunting, the Pao2 cannot be restored to normal with inspiration of 100% O2.


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InternalMed_Harrison. Anemic Hypoxia A reduction in hemoglobin concentration of the blood is accompanied by a corresponding decline in the O2-carrying capacity of the blood. Although the Pao2 is normal in anemic hypoxia, the absolute quantity of O2 transported per unit volume of blood is diminished. As the anemic blood passes through the capillaries and the usual quantity of O2 is removed from it, the Po2 and saturation in the venous blood decline to a greater extent than normal. Carbon Monoxide (CO) Intoxication (See also Chap. 472e) Hemoglobin that binds with CO (carboxy-hemoglobin, COHb) is unavailable for O2 transport. In addition, the presence of COHb shifts the Hb-O2 dissociation curve to the left (see Fig. 127-2) so that O2 is unloaded only at lower tensions, further contributing to tissue hypoxia.


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InternalMed_Harrison. Circulatory Hypoxia As in anemic hypoxia, the Pao2 is usually normal, but venous and tissue Po2 values are reduced as a consequence of reduced tissue perfusion and greater tissue O2 extraction. This pathophysiology leads to an increased arterial-mixed venous O2 difference (a-v-O2 difference), or gradient. Generalized circulatory hypoxia occurs in heart failure (Chap. 279) and in most forms of shock (Chap. 324).


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InternalMed_Harrison. Specific Organ Hypoxia Localized circulatory hypoxia may occur as a result of decreased perfusion secondary to arterial obstruction, as in localized atherosclerosis in any vascular bed, or as a consequence of vasoconstriction, as observed in Raynaud’s phenomenon (Chap. 302). Localized hypoxia may also result from venous obstruction and the resultant expansion of interstitial fluid causing arteriolar compression and, thereby, reduction of arterial inflow. Edema, which increases the distance through which O2 must diffuse before it reaches cells, can also cause localized hypoxia. In an attempt to maintain adequate perfusion to more vital organs in patients with reduced cardiac output secondary to heart failure or hypovolemic shock, vasoconstriction may reduce perfusion in the limbs and skin, causing hypoxia of these regions.


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InternalMed_Harrison. Increased O2 Requirements If the O2 consumption of tissues is elevated without a corresponding increase in perfusion, tissue hypoxia ensues and the Po2 in venous blood declines. Ordinarily, the clinical picture of patients with hypoxia due to an elevated metabolic rate, as in fever or thyrotoxicosis, is quite different from that in other types of hypoxia: the skin is warm and flushed owing to increased cutaneous blood flow that dissipates the excessive heat produced, and cyanosis is usually absent. Exercise is a classic example of increased tissue O2 requirements. These increased demands are normally met by several mechanisms operating simultaneously: (1) increase in the cardiac output and ventilation and, thus, O2 delivery to the tissues; (2) a preferential shift in blood flow to the exercising muscles by changing vascular resistances


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases in the circulatory beds of exercising tissues, directly and/or reflexly; (3) an increase in O2 extraction from the delivered blood and a widening of the arteriovenous O2 difference; and (4) a reduction in the pH of the tissues and capillary blood, shifting the Hb-O2 curve to the right (see Fig. 127-2), and unloading more O2 from hemoglobin. If the capacity of these mechanisms is exceeded, then hypoxia, especially of the exercising muscles, will result. Improper Oxygen utilization Cyanide (Chap. 473e) and several other similarly acting poisons cause cellular hypoxia. The tissues are unable to use O2, and, as a consequence, the venous blood tends to have a high O2 tension. This condition has been termed histotoxic hypoxia.


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InternalMed_Harrison. An important component of the respiratory response to hypoxia originates in special chemosensitive cells in the carotid and aortic bodies and in the respiratory center in the brainstem. The stimulation of these cells by hypoxia increases ventilation, with a loss of CO2, and can lead to respiratory alkalosis. When combined with the metabolic acidosis resulting from the production of lactic acid, the serum bicarbonate level declines (Chap. 66). With the reduction of Pao2, cerebrovascular resistance decreases and cerebral blood flow increases in an attempt to maintain O2 delivery to the brain. However, when the reduction of Pao2 is accompanied by hyperventilation and a reduction of Paco2, cerebrovascular resistance rises, cerebral blood flow falls, and tissue hypoxia intensifies.


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InternalMed_Harrison. The diffuse, systemic vasodilation that occurs in generalized hypoxia increases the cardiac output. In patients with underlying heart disease, the requirements of peripheral tissues for an increase of cardiac output with hypoxia may precipitate congestive heart failure. In patients with ischemic heart disease, a reduced Pao2 may intensify myocardial ischemia and further impair left ventricular function.


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InternalMed_Harrison. One of the important compensatory mechanisms for chronic hypoxia is an increase in the hemoglobin concentration and in the number of red blood cells in the circulating blood, i.e., the development of polycythemia secondary to erythropoietin production (Chap. 131). In persons with chronic hypoxemia secondary to prolonged residence at a high altitude (>13,000 ft, 4200 m), a condition termed chronic mountain sickness develops. This disorder is characterized by a blunted respiratory drive, reduced ventilation, erythrocytosis, cyanosis, weakness, right ventricular enlargement secondary to pulmonary hypertension, and even stupor.


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InternalMed_Harrison. Cyanosis refers to a bluish color of the skin and mucous membranes resulting from an increased quantity of reduced hemoglobin (i.e., deoxygenated hemoglobin) or of hemoglobin derivatives (e.g., met-hemoglobin or sulfhemoglobin) in the small blood vessels of those tissues. It is usually most marked in the lips, nail beds, ears, and malar eminences. Cyanosis, especially if developed recently, is more commonly detected by a family member than the patient. The florid skin characteristic of polycythemia vera (Chap. 131) must be distinguished from the true cyanosis discussed here. A cherry-colored flush, rather than cyanosis, is caused by COHb (Chap. 473e).


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InternalMed_Harrison. The degree of cyanosis is modified by the color of the cutaneous pigment and the thickness of the skin, as well as by the state of the cutaneous capillaries. The accurate clinical detection of the presence and degree of cyanosis is difficult, as proved by oximetric studies. In some instances, central cyanosis can be detected reliably when the Sao2 has fallen to 85%; in others, particularly in dark-skinned persons, it may not be detected until it has declined to 75%. In the latter case, examination of the mucous membranes in the oral cavity and the conjunctivae rather than examination of the skin is more helpful in the detection of cyanosis.


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InternalMed_Harrison. The increase in the quantity of reduced hemoglobin in the mucocutaneous vessels that produces cyanosis may be brought about either by an increase in the quantity of venous blood as a result of dilation of the venules (including precapillary venules) or by a reduction in the Sao2 in the capillary blood. In general, cyanosis becomes apparent when the concentration of reduced hemoglobin in capillary blood exceeds 40 g/L (4 g/dL).


InternalMed_Harrison

InternalMed_Harrison. It is the absolute, rather than the relative, quantity of reduced hemoglobin that is important in producing cyanosis. Thus, in a patient with severe anemia, the relative quantity of reduced hemoglobin in the venous blood may be very large when considered in relation to the total quantity of hemoglobin in the blood. However, since the concentration of the latter is markedly reduced, the absolute quantity of reduced hemoglobin may still be low, and, therefore, patients with severe anemia and even marked arterial desaturation may not display cyanosis. Conversely, the higher the total hemoglobin content, the greater the tendency toward cyanosis; thus, patients with marked polycythemia tend to be cyanotic at higher levels of Sao2 than patients with normal hematocrit values. Likewise, local passive congestion, which causes an increase in the total quantity of reduced hemoglobin in the vessels in a given area, may cause cyanosis. Cyanosis is also observed when nonfunctional hemoglobin, such


InternalMed_Harrison

InternalMed_Harrison. congestion, which causes an increase in the total quantity of reduced hemoglobin in the vessels in a given area, may cause cyanosis. Cyanosis is also observed when nonfunctional hemoglobin, such as methemoglobin (consequential or acquired) or sulfhemoglobin (Chap. 127), is present in blood.


InternalMed_Harrison

InternalMed_Harrison. Cyanosis may be subdivided into central and peripheral types. In central cyanosis, the Sao2 is reduced or an abnormal hemoglobin derivative is present, and the mucous membranes and skin are both affected. Peripheral cyanosis is due to a slowing of blood flow and abnormally great extraction of O2 from normally saturated arterial blood; it results from vasoconstriction and diminished peripheral blood flow, such as occurs in cold exposure, shock, congestive failure, and peripheral vascular disease. Often in these conditions, the mucous membranes of the oral cavity or those beneath the tongue may be spared. Clinical differentiation between central and peripheral cyanosis may not always be simple, and in conditions such as cardiogenic shock with pulmonary edema, there may be a mixture of both types.


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InternalMed_Harrison. DIFFERENTIAL DIAgNOSIS Central Cyanosis (Table 49-1) Decreased Sao2 results from a marked reduction in the Pao2. This reduction may be brought about by a decline in the Fio2 without sufficient compensatory alveolar hyperventilation to maintain alveolar Po2. Cyanosis usually becomes manifest in an ascent to an altitude of 4000 m (13,000 ft). Seriously impaired pulmonary function, through perfusion of unventilated or poorly ventilated areas of the lung or alveolar hypoventilation, is a common cause of central cyanosis (Chap. 306e). Inhomogeneity in pulmonary ventilation and perfusion (perfusion of hypoventilated alveoli) Impaired oxygen diffusion Anatomic shunts Certain types of congenital heart disease Pulmonary arteriovenous fistulas Multiple small intrapulmonary shunts Hemoglobin with low affinity for oxygen Hemoglobin abnormalities Methemoglobinemia—hereditary, acquired Sulfhemoglobinemia—acquired Carboxyhemoglobinemia (not true cyanosis)


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InternalMed_Harrison. Hemoglobin with low affinity for oxygen Hemoglobin abnormalities Methemoglobinemia—hereditary, acquired Sulfhemoglobinemia—acquired Carboxyhemoglobinemia (not true cyanosis) Reduced cardiac output Cold exposure Redistribution of blood flow from extremities Arterial obstruction Venous obstruction This condition may occur acutely, as in extensive pneumonia or 249 pulmonary edema, or chronically, with chronic pulmonary diseases (e.g., emphysema). In the latter situation, secondary polycythemia is generally present and clubbing of the fingers (see below) may occur. Another cause of reduced Sao2 is shunting of systemic venous blood into the arterial circuit. Certain forms of congenital heart disease are associated with cyanosis on this basis (see above and Chap. 282).


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InternalMed_Harrison. Pulmonary arteriovenous fistulae may be congenital or acquired, solitary or multiple, microscopic or massive. The severity of cyanosis produced by these fistulae depends on their size and number. They occur with some frequency in hereditary hemorrhagic telangiectasia. Sao2 reduction and cyanosis may also occur in some patients with cirrhosis, presumably as a consequence of pulmonary arteriovenous fistulae or portal vein–pulmonary vein anastomoses. In patients with cardiac or pulmonary right-to-left shunts, the presence and severity of cyanosis depend on the size of the shunt relative to the systemic flow as well as on the Hb-O2 saturation of the venous blood. With increased extraction of O2 from the blood by the exercising muscles, the venous blood returning to the right side of the heart is more unsaturated than at rest, and shunting of this blood intensifies the cyanosis. Secondary polycythemia occurs frequently in patients in this setting and contributes to the cyanosis.


InternalMed_Harrison

InternalMed_Harrison. Cyanosis can be caused by small quantities of circulating methemoglobin (Hb Fe3+) and by even smaller quantities of sulfhemoglobin (Chap. 127); both of these hemoglobin derivatives impair oxygen delivery to the tissues. Although they are uncommon causes of cyanosis, these abnormal hemoglobin species should be sought by spectroscopy when cyanosis is not readily explained by malfunction of the circulatory or respiratory systems. Generally, digital clubbing does not occur with them. Peripheral Cyanosis Probably the most common cause of peripheral cyanosis is the normal vasoconstriction resulting from exposure to cold air or water. When cardiac output is reduced, cutaneous vasoconstriction occurs as a compensatory mechanism so that blood is diverted from the skin to more vital areas such as the CNS and heart, and cyanosis of the extremities may result even though the arterial blood is normally saturated.


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InternalMed_Harrison. Arterial obstruction to an extremity, as with an embolus, or arteriolar constriction, as in cold-induced vasospasm (Raynaud’s phenomenon) (Chap. 302), generally results in pallor and coldness, and there may be associated cyanosis. Venous obstruction, as in thrombophlebitis or deep venous thrombosis, dilates the subpapillary venous plexuses and thereby intensifies cyanosis. APPROACH TO THE PATIENT: Certain features are important in arriving at the cause of cyanosis: 1. It is important to ascertain the time of onset of cyanosis. Cyanosis present since birth or infancy is usually due to congenital heart disease. 2. Central and peripheral cyanosis must be differentiated. Evidence of disorders of the respiratory or cardiovascular systems is helpful. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral, but not central, cyanosis. 3.


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InternalMed_Harrison. 3. The presence or absence of clubbing of the digits (see below) should be ascertained. The combination of cyanosis and clubbing is frequent in patients with congenital heart disease and right-to-left shunting and is seen occasionally in patients with pulmonary disease, such as lung abscess or pulmonary arteriovenous fistulae. In contrast, peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits. 4. Pao2 and Sao2 should be determined, and, in patients with cyanosis in whom the mechanism is obscure, spectroscopic examination of the blood should be performed to look for abnormal types of hemoglobin (critical in the differential diagnosis of cyanosis).


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InternalMed_Harrison. The selective bulbous enlargement of the distal segments of the fingers and toes due to proliferation of connective tissue, particularly on the dorsal surface, is termed clubbing; there is also increased sponginess of the soft tissue at the base of the clubbed nail. Clubbing may be hereditary, idiopathic, or acquired and associated with a variety of disorders, including cyanotic congenital heart disease (see above), infective endocarditis, and a variety of pulmonary conditions (among them primary and metastatic lung cancer, bronchiectasis, asbestosis, sarcoidosis, lung abscess, cystic fibrosis, tuberculosis, and mesothelioma), as well as with some gastrointestinal diseases (including inflammatory bowel disease and hepatic cirrhosis). In some instances, it is occupational, e.g., in jackhammer operators.


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InternalMed_Harrison. Clubbing in patients with primary and metastatic lung cancer, mesothelioma, bronchiectasis, or hepatic cirrhosis may be associated with hypertrophic osteoarthropathy. In this condition, the subperiosteal formation of new bone in the distal diaphyses of the long bones of the extremities causes pain and symmetric arthritis-like changes in the shoulders, knees, ankles, wrists, and elbows. The diagnosis of hypertrophic osteoarthropathy may be confirmed by bone radiograph or magnetic resonance imaging (MRI). Although the mechanism of clubbing is unclear, it appears to be secondary to humoral substances that cause dilation of the vessels of the distal digits as well as growth factors released from platelet precursors in the digital circulation. In certain circumstances, clubbing is reversible, such as following lung transplantation for cystic fibrosis. Eugene Braunwald, Joseph Loscalzo PART 2 Cardinal Manifestations and Presentation of Diseases


InternalMed_Harrison

InternalMed_Harrison. About one-third of total-body water is confined to the extracellular space. Approximately 75% of the latter is interstitial fluid, and the remainder is the plasma. The forces that regulate the disposition of fluid between these two components of the extracellular compartment frequently are referred to as the Starling forces. The hydrostatic pressure within the capillaries and the colloid oncotic pressure in the interstitial fluid tend to promote movement of fluid from the vascular to the extravascular space. By contrast, the colloid oncotic pressure contributed by plasma proteins and the hydrostatic pressure within the interstitial fluid promote the movement of fluid into the vascular compartment. As a consequence, there is movement of water and diffusible solutes from the vascular space at the arteriolar end of the capillaries. Fluid is returned from the interstitial space into the vascular system at the venous end of the capillaries and by way of the lymphatics. These movements are


InternalMed_Harrison

InternalMed_Harrison. at the arteriolar end of the capillaries. Fluid is returned from the interstitial space into the vascular system at the venous end of the capillaries and by way of the lymphatics. These movements are usually balanced so that there is a steady state in the sizes of the intravascular and interstitial compartments, yet a large exchange between them occurs. However, if either the capillary hydrostatic pressure is increased and/or the oncotic pressure is reduced, a further net movement of fluid from intravascular to the interstitial spaces will take place.


InternalMed_Harrison

InternalMed_Harrison. Edema is defined as a clinically apparent increase in the interstitial fluid volume, which develops when Starling forces are altered so that there is increased flow of fluid from the vascular system into the interstitium. Edema due to an increase in capillary pressure may result from an elevation of venous pressure caused by obstruction to venous and/ or lymphatic drainage. An increase in capillary pressure may be generalized, as occurs in heart failure, or it may be localized to one extremity when venous pressure is elevated due to unilateral thrombophlebitis (see below). The Starling forces also may be imbalanced when the colloid oncotic pressure of the plasma is reduced owing to any factor that may induce hypoalbuminemia, as when large quantities of protein are lost in the urine such as in the nephrotic syndrome (see below), or when synthesis is reduced in a severe catabolic state.


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InternalMed_Harrison. Edema may also result from damage to the capillary endothelium, which increases its permeability and permits the transfer of proteins into the interstitial compartment. Injury to the capillary wall can result from drugs (see below), viral or bacterial agents, and thermal or mechanical trauma. Increased capillary permeability also may be a consequence of a hypersensitivity reaction and of immune injury. Damage to the capillary endothelium is presumably responsible for inflammatory edema, which is usually nonpitting, localized, and accompanied by other signs of inflammation—i.e., erythema, heat, and tenderness.


InternalMed_Harrison

InternalMed_Harrison. In many forms of edema, despite the increase in extracellular fluid volume, the effective arterial blood volume, a parameter that represents the filling of the arterial tree and that effectively perfuses the tissues, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance, by pooling of blood in the splanchnic veins (as in cirrhosis), and by hypoalbuminemia (Fig. 50-1A). As a consequence of underfilling, a series of physiologic responses designed to restore the effective arterial volume to normal are set into motion. A key element of these responses is the renal retention of sodium and, therefore, water, thereby restoring effective arterial volume, but sometimes also leading to or intensifying edema.


InternalMed_Harrison

InternalMed_Harrison. The diminished renal blood flow characteristic of states in which the effective arterial blood volume is reduced is translated by the renal juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release. Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its substrate, angiotensinogen, an α2-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which in turn is converted to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties, particularly on the renal efferent arterioles. This action reduces the hydrostatic pressure in the peritubular capillaries, whereas the increased filtration fraction raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle.


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InternalMed_Harrison. The renin-angiotensin-aldosterone system (RAAS) operates as both a hormonal and paracrine system. Its activation causes sodium and water retention and thereby contributes to edema formation. Blockade of the conversion of angiotensin I to AII and blockade of the AII receptor enhance sodium and water excretion and reduce many forms of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone in turn enhances sodium reabsorption (and potassium excretion) by the collecting tubule, further favoring edema formation. In patients with heart failure, not only is aldosterone secretion elevated but the biologic half-life of the hormone is prolonged secondary to the depression of hepatic blood flow, which reduces its hepatic catabolism and increases further the plasma level of the hormone. Blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a


InternalMed_Harrison

InternalMed_Harrison. its hepatic catabolism and increases further the plasma level of the hormone. Blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a blocker of epithelial sodium channels) often induces a moderate diuresis in edematous states.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 404) The secretion of arginine vasopressin (AVP) occurs in response to increased intracellular osmolar concentration, and, by stimulating V2 receptors, AVP increases the reabsorption of free water in the distal tubules and collecting ducts of the kidneys, thereby increasing total-body water. Circulating AVP is elevated in many patients with heart failure secondary to a nonosmotic stimulus associated with decreased effective arterial volume and reduced compliance of the left atrium. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia.


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InternalMed_Harrison. Nonosmotic vasopressin stimulation Activation of RAAS ˜Extracellular fluid volume ˜Cardiac output Effective arterial volume Activation of ventricular and arterial receptors Restoration of effective arterial volume SNS stimulation Renal H2O retention Renal Na+ retention Low output heart failure, Pericardial tamponade Constructive pericarditis ˜Oncotic pressure and/or °capillary permeability °Systemic and renal arterial vascular resistance Sepsis Cirrhosis Activation of RAAS High-output cardiac failure Arteriovenous fistula Arterial vasodilators ˜Systemic vascular resistance Effective arterial volume Maintenance of arterial circulatory integrity Activation of arterial baroreceptors Nonosmotic AVP stimulation °Cardiac output Renal H2O retention SNS stimulation Pregnancy Renal Na+ retention °Systemic arterial, vascular, and renal resistance


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InternalMed_Harrison. FIguRE 50-1 Clinical conditions in which a decrease in cardiac output (A) and systemic vascular resistance (B) cause arterial underfilling with resulting neurohumoral activation and renal sodium and water retention. In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. RAAS, renin-angiotensin aldosterone system; SNS, sympathetic nervous system. (Modified from RW Schrier: Ann Intern Med 113:155, 1990.) This potent peptide vasoconstrictor is released by endothelial cells. Its concentration in the plasma is elevated in patients with severe heart failure and contributes to renal vasoconstriction, sodium retention, and edema.


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InternalMed_Harrison. Atrial distention causes release into the circulation of atrial natriuretic peptide (ANP), a polypeptide; a high-molecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. The closely related brain natriuretic peptide (pre-prohor-251 mone BNP) is stored primarily in ventricular myocytes and is released when ventricular diastolic pressure rises. Released ANP and BNP (which is derived from its precursor) bind to the natriuretic receptor-A, which causes: (1) excretion of sodium and water by augmenting glomerular filtration rate, inhibiting sodium reabsorption in the proximal tubule, and inhibiting release of renin and aldosterone; and (2) dilation of arterioles and venules by antagonizing the vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, elevated levels of natriuretic peptides have the capacity to oppose sodium retention in hypervolemic and edematous states.


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InternalMed_Harrison. Although circulating levels of ANP and BNP are elevated in heart failure and in cirrhosis with ascites, the natriuretic peptides are not sufficiently potent to prevent edema formation. Indeed, in edematous states, resistance to the actions of natriuretic peptides may be increased, further reducing their effectiveness. Further discussion of the control of sodium and water balance is found in Chap. 64e. A weight gain of several kilograms usually precedes overt manifestations of generalized edema, and a similar weight loss from diuresis can be induced in a slightly edematous patient before “dry weight” is achieved. Anasarca refers to gross, generalized edema. Ascites (Chap. 59) and hydrothorax refer to accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered special forms of edema.


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InternalMed_Harrison. Edema is recognized by the persistence of an indentation of the skin after pressure; this is known as “pitting” edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. Edema may be present when the ring on a finger fits more snugly than in the past or when a patient complains of difficulty putting on shoes, particularly in the evening. Edema may also be recognized by puffiness of the face, which is most readily apparent in the periorbital areas. The differences among the major causes of generalized edema are shown in Table 50-1. Cardiac, renal, hepatic, or nutritional disorders are responsible for a majority of patients with generalized edema. Consequently, the differential diagnosis of generalized edema should be directed toward identifying or excluding these several conditions.


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InternalMed_Harrison. Heart Failure (See also Chap. 279) In heart failure, the impaired systolic emptying of the ventricle(s) and/or the impairment of ventricular relaxation promotes an accumulation of blood in the venous circulation at the expense of the effective arterial volume. In addition, the heightened tone of the sympathetic nervous system causes renal vasoconstriction and reduction of glomerular filtration. In mild heart failure, a small increment of total blood volume may repair the deficit of 252 TABLE 50-1 PRinCiPAL CAuSES of gEnERALizED EDEMA: HiSToRy, PHySiCAL ExAMinATion, AnD LABoRAToRy finDingS PART 2 Cardinal Manifestations and Presentation of Diseases Renal (CRF) Usually chronic: may be associated with uremic signs and symptoms, including decreased appetite, altered (metallic or fishy) taste, altered sleep pattern, difficulty concentrating, restless legs, or myoclonus; dyspnea can be present, but generally less prominent than in heart failure


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InternalMed_Harrison. Abbreviations: CRF, chronic renal failure; NS, nephrotic syndrome. Elevated jugular venous pressure, ventricular (S3) gallop; occasionally with displaced or dyskinetic apical pulse; peripheral cyanosis, cool extremities, small pulse pressure when severe Frequently associated with ascites; jugular venous pressure normal or low; blood pressure lower than in renal or cardiac disease; one or more additional signs of chronic liver disease (jaundice, palmar erythema, Dupuytren’s contracture, spider angiomata, male gynecomastia; asterixis and other signs of encephalopathy) may be present Elevated blood pressure; hypertensive retinopathy; nitrogenous fetor; pericardial friction rub in advanced cases with uremia If severe, reductions in serum albumin, cholesterol, other hepatic proteins (transferrin, fibrinogen); liver enzymes elevated, depending on the cause and acuity of liver injury; tendency toward hypokalemia, respiratory alkalosis; macrocytosis from folate deficiency


InternalMed_Harrison

InternalMed_Harrison. Elevation of serum creatinine and cystatin C; albuminuria; hyperkalemia, metabolic acidosis, hyperphosphatemia, hypocalcemia, anemia (usually normocytic) Proteinuria (≥3.5 g/d); hypoalbuminemia; hypercholesterolemia; microscopic hematuria Source: Modified from GM Chertow: Approach to the patient with edema, in Primary Cardiology, 2nd ed, E Braunwald, L Goldman (eds). Philadelphia, Saunders, 2003, pp 117–128. effective arterial volume through the operation of Starling’s law of the heart, in which an increase in ventricular diastolic volume promotes a more forceful contraction and may thereby maintain the cardiac output. However, if the cardiac disorder is more severe, sodium and water retention continue, and the increment in blood volume accumulates in the venous circulation, raising venous pressure and causing edema (Fig. 50-1).


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InternalMed_Harrison. The presence of heart disease, as manifested by cardiac enlargement and/or ventricular hypertrophy, together with evidence of cardiac failure, such as dyspnea, basilar rales, venous distention, and hepatomegaly, usually indicates that edema results from heart failure. Noninvasive tests such as echocardiography may be helpful in establishing the diagnosis of heart disease. The edema of heart failure typically occurs in the dependent portions of the body.


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InternalMed_Harrison. Edema of Renal Disease (See also Chap. 338) The edema that occurs during the acute phase of glomerulonephritis is characteristically associated with hematuria, proteinuria, and hypertension. Although some evidence supports the view that the fluid retention is due to increased capillary permeability, in most instances, the edema results from primary retention of sodium and water by the kidneys owing to renal insufficiency. This state differs from most forms of heart failure in that it is characterized by a normal (or sometimes even increased) cardiac output. Patients with edema due to acute renal failure commonly have arterial hypertension as well as pulmonary congestion on chest roentgenogram, often without considerable cardiac enlargement, but they may not develop orthopnea. Patients with chronic renal failure may also develop edema due to primary renal retention of sodium and water.


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InternalMed_Harrison. Nephrotic Syndrome and other Hypoalbuminemic States The primary alteration in the nephrotic syndrome is a diminished colloid oncotic pressure due to losses of large quantities (≥3.5 g/d) of protein into the urine. With severe hypoalbuminemia (<35 g/L) and the consequent reduced colloid osmotic pressure, the sodium and water that are retained cannot be restrained within the vascular compartment, and total and effective arterial blood volumes decline. This process initiates the edema-forming sequence of events described above, including activation of the RAAS. The nephrotic syndrome may occur during the course of a variety of kidney diseases, which include glomerulonephritis, diabetic glomerulosclerosis, and hypersensitivity reactions. The edema is diffuse, symmetric, and most prominent in the dependent areas; as a consequence, periorbital edema is most prominent in the morning.


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InternalMed_Harrison. Hepatic Cirrhosis (See also Chap. 365) This condition is characterized in part by hepatic venous outflow blockade, which in turn expands the splanchnic blood volume and increases hepatic lymph formation. Intrahepatic hypertension acts as a stimulus for renal sodium retention and causes a reduction of effective arterial blood volume. These alterations are frequently complicated by hypoalbuminemia secondary to reduced hepatic synthesis of albumin, as well as peripheral arterial vasodilation. These effects reduce the effective arterial blood volume further, leading to activation of the RAAS and renal sympathetic nerves and to release of AVP, endothelin, and other sodium-and water-retaining mechanisms (Fig. 50-1B). The concentration of circulating aldosterone often is elevated by the failure of the liver to metabolize this hormone. Initially, the excess interstitial fluid is localized preferentially proximal (upstream) to the congested portal venous system and obstructed hepatic


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InternalMed_Harrison. failure of the liver to metabolize this hormone. Initially, the excess interstitial fluid is localized preferentially proximal (upstream) to the congested portal venous system and obstructed hepatic lymphatics, i.e., in the peritoneal cavity (causing ascites, Chap. 59). In later stages, particularly when there is severe hypoalbuminemia, peripheral edema may develop. A sizable accumulation of ascitic fluid may increase intraabdominal pressure and impede venous return from the lower extremities and contribute to the accumulation of edema of the lower extremities.


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InternalMed_Harrison. The excess production of prostaglandins (PGE2 and PGI2) in cirrhosis attenuates renal sodium retention. When the synthesis of these substances is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs), renal function may deteriorate, and this may increase sodium retention further. Drug-Induced Edema A large number of widely used drugs can cause edema (Table 50-2). Mechanisms include renal vasoconstriction (NSAIDs and cyclosporine), arteriolar dilation (vasodilators), augmented renal sodium reabsorption (steroid hormones), and capillary damage.


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InternalMed_Harrison. Edema of Nutritional Origin A diet grossly deficient in protein over a prolonged period may produce hypoproteinemia and edema. The latter may be intensified by the development of beriberi heart disease, which also is of nutritional origin, in which multiple peripheral arteriovenous fistulae result in reduced effective systemic perfusion and effective arterial blood volume, thereby enhancing edema formation (Chap. 96e) (Fig. 50-1B). Edema may actually become intensified OKT3 monoclonal antibody Source: Modified from Chertow GM: Approach to the patient with edema, in Primary Cardiology, 2nd ed, E Braunwald, L Goldman (eds). Philadelphia, Saunders, 2003, pp 117–128.


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InternalMed_Harrison. OKT3 monoclonal antibody Source: Modified from Chertow GM: Approach to the patient with edema, in Primary Cardiology, 2nd ed, E Braunwald, L Goldman (eds). Philadelphia, Saunders, 2003, pp 117–128. when famished subjects are first provided with an adequate diet. The ingestion of more food may increase the quantity of sodium ingested, which is then retained along with water. So-called refeeding edema also may be linked to increased release of insulin, which directly increases tubular sodium reabsorption. In addition to hypoalbuminemia, hypokalemia and caloric deficits may be involved in the edema of starvation.


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InternalMed_Harrison. In this condition, the hydrostatic pressure in the capillary bed upstream (proximal) of the obstruction increases so that an abnormal quantity of fluid is transferred from the vascular to the interstitial space. Since the alternative route (i.e., the lymphatic channels) also may be obstructed or maximally filled, an increased volume of interstitial fluid in the limb develops (i.e., there is trapping of fluid in the interstitium of the extremity). The displacement of large quantities of fluid into a limb may occur at the expense of the blood volume in the remainder of the body, thereby reducing effective arterial blood volume and leading to the retention of NaCl and H2O until the deficit in plasma volume has been corrected.


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InternalMed_Harrison. Localized edema due to venous or lymphatic obstruction may be caused by thrombophlebitis, chronic lymphangitis, resection of regional lymph nodes, and filariasis, among other causes. Lymphedema is particularly intractable because restriction of lymphatic flow results in increased protein concentration in the interstitial fluid, a circumstance that aggravates fluid retention. Other Causes of Edema These causes include hypothyroidism (myxedema) and hyperthyroidism (pretibial myxedema secondary to Graves’ disease), the edema in which is typically nonpitting and due to deposition of hyaluronic acid and, in Graves’ disease, lymphocytic infiltration and inflammation; exogenous hyperadrenocortism; pregnancy; and administration of estrogens and vasodilators, particularly dihydropyridines such as nifedipine.


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InternalMed_Harrison. The distribution of edema is an important guide to its cause. Edema associated with heart failure tends to be more extensive in the legs and to be accentuated in the evening, a feature also determined largely by posture. When patients with heart failure are confined to bed, edema 253 may be most prominent in the presacral region. Severe heart failure may cause ascites that may be distinguished from the ascites caused by hepatic cirrhosis by the jugular venous pressure, which is usually elevated in heart failure and normal in cirrhosis.


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InternalMed_Harrison. Edema resulting from hypoproteinemia, as occurs in the nephrotic syndrome, characteristically is generalized, but it is especially evident in the very soft tissues of the eyelids and face and tends to be most pronounced in the morning owing to the recumbent posture assumed during the night. Less common causes of facial edema include trichinosis, allergic reactions, and myxedema. Edema limited to one leg or to one or both arms is usually the result of venous and/or lymphatic obstruction. Unilateral paralysis reduces lymphatic and venous drainage on the affected side and may also be responsible for unilateral edema. In patients with obstruction of the superior vena cava, edema is confined to the face, neck, and upper extremities in which the venous pressure is elevated compared with that in the lower extremities. APPROACH TO THE PATIENT: CHAPTER 51e Approach to the Patient with a Heart Murmur


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InternalMed_Harrison. APPROACH TO THE PATIENT: CHAPTER 51e Approach to the Patient with a Heart Murmur An important first question is whether the edema is localized or generalized. If it is localized, the local phenomena that may be responsible should be considered. If the edema is generalized, one should first determine if there is serious hypoalbuminemia, e.g., serum albumin <25 g/L. If so, the history, physical examination, urinalysis, and other laboratory data will help evaluate the question of cirrhosis, severe malnutrition, or the nephrotic syndrome as the underlying disorder. If hypoalbuminemia is not present, it should be determined if there is evidence of heart failure severe enough to promote generalized edema. Finally, it should be ascertained as to whether or not the patient has an adequate urine output or if there is significant oliguria or anuria. These abnormalities are discussed in Chaps. 61, 334, and 335. Approach to the Patient with a Patrick T. O’Gara, Joseph Loscalzo


InternalMed_Harrison

InternalMed_Harrison. Approach to the Patient with a Patrick T. O’Gara, Joseph Loscalzo This is a digital-only chapter. it is available on the DvD that accompanies this book, as well as on Access Medicine/Harrison’s online, and the eBook and “app” editions of HPiM 19e. The differential diagnosis of a heart murmur begins with a careful assessment of its major attributes and response to bedside maneuvers. The history, clinical context, and associated physical examination findings provide additional clues by which the significance of a heart murmur can be established. Accurate bedside identification of a heart murmur can inform decisions regarding the indications for noninvasive testing and the need for referral to a cardiovascular specialist. Preliminary discussions can be held with the patient regarding antibiotic or rheumatic fever prophylaxis, the need to restrict various forms of physical activity, and the potential role for family screening.


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InternalMed_Harrison. Approach to the Patient with a Heart Murmur Patrick T. O’Gara, Joseph Loscalzo The differential diagnosis of a heart murmur begins with a careful assessment of its major attributes and response to bedside maneuvers. 51e The history, clinical context, and associated physical examination findings provide additional clues by which the significance of a heart murmur can be established. Accurate bedside identification of a heart murmur can inform decisions regarding the indications for noninvasive testing and the need for referral to a cardiovascular specialist. Preliminary discussions can be held with the patient regarding antibiotic or rheumatic fever prophylaxis, the need to restrict various forms of physical activity, and the potential role for family screening.


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InternalMed_Harrison. Heart murmurs are caused by audible vibrations that are due to increased turbulence from accelerated blood flow through normal or abnormal orifices, flow through a narrowed or irregular orifice into a dilated vessel or chamber, or backward flow through an incompetent valve, ventricular septal defect, or patent ductus arteriosus. They traditionally are defined in terms of their timing within the cardiac cycle (Fig. 51e-1). Systolic murmurs begin with or after the first heart sound (S1) and terminate at or before the component (A2 or P2) of the second heart sound (S2) that corresponds to their site of origin (left or right, respectively). Diastolic murmurs begin with or after the associated component of S2 and end at or before the subsequent S1. Continuous murmurs are not confined to either phase of the cardiac cycle but instead begin in early systole and proceed through S2 into all or part of diastole. The accurate timing of heart murmurs is the first step in their identification. The


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InternalMed_Harrison. phase of the cardiac cycle but instead begin in early systole and proceed through S2 into all or part of diastole. The accurate timing of heart murmurs is the first step in their identification. The distinction between S1 and S2 and, therefore, systole and diastole is usually a straightforward process but can be difficult in the setting of a tachyarrhythmia, in which case the heart sounds can be distinguished by simultaneous palpation of the carotid upstroke, which should closely follow S1.


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InternalMed_Harrison. Duration and Character The duration of a heart murmur depends on the length of time over which a pressure difference exists between two cardiac chambers, the left ventricle and the aorta, the right ventricle and the pulmonary artery, or the great vessels. The magnitude and variability of this pressure difference, coupled with the geometry and compliance of the involved chambers or vessels, dictate the velocity of flow; the degree of turbulence; and the resulting frequency, configuration, and intensity of the murmur. The diastolic murmur of chronic aortic regurgitation (AR) is a blowing, high-frequency event, whereas the murmur of mitral stenosis (MS), indicative of the left atrial–left ventricular diastolic pressure gradient, is a low-frequency event, heard as a rumbling sound with the bell of the stethoscope. The frequency components of a heart murmur may vary at different sites of auscultation. The coarse systolic murmur of aortic stenosis (AS) may sound higher pitched and more


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InternalMed_Harrison. bell of the stethoscope. The frequency components of a heart murmur may vary at different sites of auscultation. The coarse systolic murmur of aortic stenosis (AS) may sound higher pitched and more acoustically pure at the apex, a phenomenon eponymously referred to as the Gallavardin effect. Some murmurs may have a distinct or unusual quality, such as the “honking” sound appreciated in some patients with mitral regurgitation (MR) due to mitral valve prolapse (MVP).


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InternalMed_Harrison. The configuration of a heart murmur may be described as crescendo, decrescendo, crescendo-decrescendo, or plateau. The decrescendo configuration of the murmur of chronic AR (Fig. 51e-1E) can be understood in terms of the progressive decline in the diastolic pressure gradient between the aorta and the left ventricle. The crescendo-decrescendo configuration of the murmur of AS reflects the changes in the systolic pressure gradient between the left ventricle and the aorta as ejection occurs, whereas the plateau configuration of the murmur of chronic MR (Fig. 51e-1B) is consistent with the large and nearly constant pressure difference between the left ventricle and the left atrium. Intensity The intensity of a heart murmur is graded on a scale of 1–6 (or I–VI). A grade 1 murmur is very soft and is heard only with great


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InternalMed_Harrison. Intensity The intensity of a heart murmur is graded on a scale of 1–6 (or I–VI). A grade 1 murmur is very soft and is heard only with great FIguRe 51e-1 Diagram depicting principal heart murmurs. A. Presystolic murmur of mitral or tricuspid stenosis. B. Holosystolic (pan-systolic) murmur of mitral or tricuspid regurgitation or of ventricular septal defect. C. Aortic ejection murmur beginning with an ejection click and fading before the second heart sound. D. Systolic murmur in pulmonic stenosis spilling through the aortic second sound, pulmonic valve closure being delayed. E. Aortic or pulmonary diastolic murmur. F. Long diastolic murmur of mitral stenosis after the opening snap (OS). G. Short mid-diastolic inflow murmur after a third heart sound.


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InternalMed_Harrison. H. Continuous murmur of patent ductus arteriosus. (Adapted from P Wood: Diseases of the Heart and Circulation, London, Eyre & Spottiswood, 1968. Permission granted courtesy of Antony and Julie Wood.) effort. A grade 2 murmur is easily heard but not particularly loud. A grade 3 murmur is loud but is not accompanied by a palpable thrill over the site of maximal intensity. A grade 4 murmur is very loud and is accompanied by a thrill. A grade 5 murmur is loud enough to be heard with only the edge of the stethoscope touching the chest, whereas a grade 6 murmur is loud enough to be heard with the stethoscope slightly off the chest. Murmurs of grade 3 or greater intensity usually signify important structural heart disease and indicate high blood flow velocity at the site of murmur production. Small ventricular septal defects (VSDs), for example, are accompanied by loud, usually grade 4 or greater, systolic murmurs as blood is ejected at high velocity from the left ventricle to the right


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InternalMed_Harrison. Small ventricular septal defects (VSDs), for example, are accompanied by loud, usually grade 4 or greater, systolic murmurs as blood is ejected at high velocity from the left ventricle to the right ventricle. Low-velocity events, such as left-to-right shunting across an atrial septal defect (ASD), are usually silent. The intensity of a heart murmur may be diminished by any process that increases the distance between the intracardiac source and the stethoscope on the chest wall, such as obesity, obstructive lung disease, and a large pericardial effusion. The intensity of a murmur also may be misleadingly soft when cardiac output is reduced significantly or when the pressure gradient between the involved cardiac structures is low.


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InternalMed_Harrison. Location and Radiation Recognition of the location and radiation of the murmur helps facilitate its accurate identification (Fig. 51e-2). Adventitious sounds, such as a systolic click or diastolic snap, or abnormalities of S1 or S2 may provide additional clues. Careful attention to the characteristics of the murmur and other heart sounds CHAPTER 51e Approach to the Patient with a Heart Murmur PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. CHAPTER 51e Approach to the Patient with a Heart Murmur PART 2 Cardinal Manifestations and Presentation of Diseases FIguRe 51e-2 Maximal intensity and radiation of six isolated systolic murmurs. HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; Pulm, pulmonary stenosis; Aortic, aortic stenosis; VSD, ventricular septal defect. (From JB Barlow: Perspectives on the Mitral Valve. Philadelphia, FA Davis, 1987, p 140.) during the respiratory cycle and the performance of simple bedside maneuvers complete the auscultatory examination. These features, along with recommendations for further testing, are discussed below in the context of specific systolic, diastolic, and continuous heart murmurs (Table 51e-1).


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InternalMed_Harrison. SYSTOLIC HeART MuRMuRS early Systolic Murmurs Early systolic murmurs begin with S1 and extend for a variable period, ending well before S2. Their causes are relatively few in number. Acute, severe MR into a normal-sized, relatively noncompliant left atrium results in an early, decrescendo systolic murmur best heard at or just medial to the apical impulse. These characteristics reflect the progressive attenuation of the pressure gradient between the left ventricle and the left atrium during systole owing to the rapid rise in left atrial pressure caused by the sudden volume load into an unprepared, noncompliant chamber and contrast sharply with the auscultatory features of chronic MR. Clinical settings in which acute, severe MR occur include (1) papillary muscle rupture complicating acute myocardial infarction (MI) (Chap. 295), (2) rupture of chordae tendineae in the setting of myxomatous mitral valve disease (MVP, Chap. 283), (3) infective endocarditis (Chap. 155), and (4) blunt chest


InternalMed_Harrison

InternalMed_Harrison. infarction (MI) (Chap. 295), (2) rupture of chordae tendineae in the setting of myxomatous mitral valve disease (MVP, Chap. 283), (3) infective endocarditis (Chap. 155), and (4) blunt chest wall trauma.


InternalMed_Harrison

InternalMed_Harrison. Acute, severe MR from papillary muscle rupture usually accompanies an inferior, posterior, or lateral MI and occurs 2–7 days after presentation. It often is signaled by chest pain, hypotension, and pulmonary edema, but a murmur may be absent in up to 50% of cases. The posteromedial papillary muscle is involved 6 to 10 times more frequently than the anterolateral papillary muscle. The murmur is to be distinguished from that associated with post-MI ventricular septal rupture, which is accompanied by a systolic thrill at the left sternal border in nearly all patients and is holosystolic in duration. A new heart murmur after an MI is an indication for transthoracic echocardiography (TTE) (Chap. 270e), which allows bedside delineation of its etiology and pathophysiologic significance. The distinction between acute MR and ventricular septal rupture also can be achieved with right heart catheterization, sequential determination of oxygen saturations, and analysis of the pressure waveforms


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InternalMed_Harrison. between acute MR and ventricular septal rupture also can be achieved with right heart catheterization, sequential determination of oxygen saturations, and analysis of the pressure waveforms (tall v wave in the pulmonary artery wedge pressure in MR). Post-MI mechanical complications of this nature mandate aggressive medical stabilization and prompt referral for surgical repair.


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InternalMed_Harrison. Spontaneous chordal rupture can complicate the course of myxomatous mitral valve disease (MVP) and result in new-onset or “acute on chronic” severe MR. MVP may occur as an isolated phenomenon, or the lesion may be part of a more generalized connective tissue disorder as seen, for example, in patients with Marfan syndrome. Acute, severe MR as a consequence of infective endocarditis results from destruction of leaflet tissue, chordal rupture, or both. Blunt chest wall trauma is usually self-evident but may be disarmingly trivial; it VSD Muscular Nonrestrictive with pulmonary hypertension Tricuspid TR with normal pulmonary artery pressure Mid-systolic Aortic Obstructive Supravalvular–supravalvular aortic stenosis, coarctation of the aorta Valvular–AS and aortic sclerosis Subvalvular–discrete, tunnel or HOCM Increased flow, hyperkinetic states, AR, complete heart block Dilation of ascending aorta, atheroma, aortitis Pulmonary


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InternalMed_Harrison. Increased flow, hyperkinetic states, AR, complete heart block Dilation of ascending aorta, atheroma, aortitis Pulmonary Increased flow, hyperkinetic states, left-to-right shunt (e.g., ASD) Dilation of pulmonary artery Late systolic Mitral MVP, acute myocardial ischemia Tricuspid TVP Holosystolic Atrioventricular valve regurgitation (MR, TR) Left-to-right shunt at ventricular level (VSD) Valvular: congenital (bicuspid valve), rheumatic deformity, endocarditis, prolapse, trauma, post-valvulotomy Dilation of valve ring: aorta dissection, annuloaortic ectasia, cystic medial degeneration, hypertension, ankylosing spondylitis Widening of commissures: syphilis


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InternalMed_Harrison. Pulmonic regurgitation Valvular: post-valvulotomy, endocarditis, rheumatic fever, carcinoid Dilation of valve ring: pulmonary hypertension; Marfan syndrome Congenital: isolated or associated with tetralogy of Fallot, VSD, pulmonic stenosis fever) Increased flow across nonstenotic mitral valve (e.g., MR, VSD, PDA, high-output states, and complete heart block) Tricuspid Tricuspid stenosis Increased flow across nonstenotic tricuspid valve (e.g., TR, ASD, and anomalous pulmonary venous return) Coronary AV fistula Mammary souffle of pregnancy Ruptured sinus of Valsalva aneurysm Pulmonary artery branch stenosis Cervical venous hum Small (restrictive) ASD with MS


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InternalMed_Harrison. Coronary AV fistula Mammary souffle of pregnancy Ruptured sinus of Valsalva aneurysm Pulmonary artery branch stenosis Cervical venous hum Small (restrictive) ASD with MS Anomalous left coronary artery Intercostal AV fistula Abbreviations: AR, aortic regurgitation; AS, aortic stenosis; ASD, atrial septal defect; AV, arteriovenous; HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; MS, mitral stenosis; MVP, mitral valve prolapse; PDA, patent ductus arteriosus; TR, tricuspid regurgitation; TVP, tricuspid valve prolapse; VSD, ventricular septal defect. Source: E Braunwald, JK Perloff, in D Zipes et al (eds): Braunwald’s Heart Disease, 7th ed. Philadelphia, Elsevier, 2005; PJ Norton, RA O’Rourke, in E Braunwald, L Goldman (eds): Primary Cardiology, 2nd ed. Philadelphia, Elsevier, 2003.


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InternalMed_Harrison. can result in papillary muscle contusion and rupture, chordal detachment, or leaflet avulsion. TTE is indicated in all cases of suspected acute, severe MR to define its mechanism and severity, delineate left ventricular size and systolic function, and provide an assessment of suitability for primary valve repair.


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InternalMed_Harrison. A congenital, small muscular VSD (Chap. 282) may be associated with an early systolic murmur. The defect closes progressively during septal contraction, and thus, the murmur is confined to early systole. It is localized to the left sternal border (Fig. 51e-2) and is usually of grade 4 or 5 intensity. Signs of pulmonary hypertension or left ventricular volume overload are absent. Anatomically large and uncorrected VSDs, which usually involve the membranous portion of the septum, may lead to pulmonary hypertension. The murmur associated with the left-to-right shunt, which earlier may have been holosystolic, becomes limited to the first portion of systole as the elevated pulmonary vascular resistance leads to an abrupt rise in right ventricular pressure and an attenuation of the interventricular pressure gradient during the remainder of the cardiac cycle. In such instances, signs of pulmonary hypertension (right ventricular lift, loud and single or closely split S2) may predominate. The


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InternalMed_Harrison. pressure gradient during the remainder of the cardiac cycle. In such instances, signs of pulmonary hypertension (right ventricular lift, loud and single or closely split S2) may predominate. The murmur is best heard along the left sternal border but is softer. Suspicion of a VSD is an indication for TTE.


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InternalMed_Harrison. Tricuspid regurgitation (TR) with normal pulmonary artery pressures, as may occur with infective endocarditis, may produce an early systolic murmur. The murmur is soft (grade 1 or 2), is best heard at the lower left sternal border, and may increase in intensity with inspiration (Carvallo’s sign). Regurgitant “c-v” waves may be visible in the jugular venous pulse. TR in this setting is not associated with signs of right heart failure. Mid-Systolic Murmurs Mid-systolic murmurs begin at a short interval after , end before S (Fig. 51e-1C), and are usually crescendo-decrescendo in configuration. Aortic stenosis is the most common cause of a mid-systolic murmur in an adult. The murmur of AS is usually loudest to the right of the sternum in the second intercostal space (aortic area, Fig. 51e-2) and radiates into the carotids. Transmission of the mid-systolic murmur to the apex, where it becomes higher-pitched, is common (Gallavardin effect; see above).


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InternalMed_Harrison. Differentiation of this apical systolic murmur from MR can be difficult. The murmur of AS will increase in intensity, or become louder, in the beat after a premature beat, whereas the murmur of MR will have constant intensity from beat to beat. The intensity of the AS murmur also varies directly with the cardiac output. With a normal cardiac output, a systolic thrill and a grade 4 or higher murmur suggest severe AS. The murmur is softer in the setting of heart failure and low cardiac output. Other auscultatory findings of severe AS include a soft or absent A2, paradoxical splitting of S2, an apical S4, and a late-peaking systolic murmur. In children, adolescents, and young adults with congenital valvular AS, an early ejection sound (click) is usually audible, more often along the left sternal border than at the base. Its presence signifies a flexible, noncalcified bicuspid valve (or one of its variants) and localizes the left ventricular outflow obstruction to the valvular (rather


InternalMed_Harrison

InternalMed_Harrison. sternal border than at the base. Its presence signifies a flexible, noncalcified bicuspid valve (or one of its variants) and localizes the left ventricular outflow obstruction to the valvular (rather than subor supravalvular) level.


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InternalMed_Harrison. Assessment of the volume and rate of rise of the carotid pulse can provide additional information. A small and delayed upstroke (parvus et tardus) is consistent with severe AS. The carotid pulse examination is less discriminatory, however, in older patients with stiffened arteries. The electrocardiogram (ECG) shows signs of left ventricular hypertrophy (LVH) as the severity of the stenosis increases. TTE is indicated to assess the anatomic features of the aortic valve, the severity of the stenosis, left ventricular size, wall thickness and function, and the size and contour of the aortic root and proximal ascending aorta.