key: cord-0698483-iwcync0o authors: Brenner, Barry E. title: Bronchial asthma in adults: Presentation to the emergency department Part I: Pathogenesis, clinical manifestations, diagnostic evaluation, and differential diagnosis date: 1983-07-31 journal: The American Journal of Emergency Medicine DOI: 10.1016/0735-6757(83)90038-4 sha: 674b76f0a699bac08a210fc9ffe8be4c67b9f24d doc_id: 698483 cord_uid: iwcync0o nan The first five minutes of the presentation of an acute asthmatic to a medical center are unique to emergency medicine. A brief disease-oriented history and physical are mandatory, as diagnostic and therapeutic decisions must be made quickly. In asthma, these first five minutes may mean the difference between a patient's discharge home, admission, intubation, or resuscitation from a cardiac or respiratory arrest. Asthma is a well-studied disorder about which much experimental and clinical information is available, however, few illnesses have a treatment plan that varies so greatly between different practitioners and institutions. ' Physicians agree that the management of an Extrinsic asthma is understood as reversible bronchospasm due to allergens.2-4 One important mechanism underlying extrinsic asthma is immediate hypersensitivity (Type 11 in which an antibody, IgE, reacts with an allergen and activates intramembranous methyltransferase which converts phosphatidyl ethanolamine to phosphatidyl choline and which is associated with the reorientation or translocation of membrane phosphatidyls and then the influx of extracellular calcium. Calcium activates intramembranous phospholipase A, (EC 3.1.1.4) which acts on membrane lipids and forms arachidonic acid in the intracellular space. The arachidonic acid is metabolized either by cyclooxygenase to form vasoactive prostaglandins (thromboxanes, prostacyclins), or by lipoxygenase (EC 1.13.11.121 to form hydroperoxy-eicosatetraenoic acid (HPETE) which is the precursor for the leukotrienes. Leukotrienes (LT\ are enumerated A through E presently and the subscript 4 denotes the number of double bonds ( Figure 1 ). LTB, has very potent chemotactic activity, and LTC,, LTD,, and LTE, are, in descending order of potency, smooth muscle contractors in vitro and comprise activity formerly referred to as "slow reacting substance of anaphylaxis (SRS-A) .' #' Histamines and bradykinins are also released culminating in bronchospasm. Another mechanism for allergy occurs from a slower type of hypersensitivity jType III). In this mechanism, the antibody IgG combines with dusts, frequently occupational, to form an immune complex that activates the complement system. Fragments of complement jC3a and C5al may mediate histamine release.6 These processes cause bronchial edema, tenacious viscid secretions, mucus of phospholipids resulting in the influx of extracellular calcium. In addition, phosphatidyl ethanolamine is methylated and translocated to the extramembranous region. The calcium influx activates phospholipase A, which acts on membrane lipids and forms arachidonic acid in the intracellular space. Arachidonic acid is metabolized by either lipoxygenase to form HPETE and leukotrienes (LT) or by cyclooxygenase to form vasoactive thromboxanes and prostacyclins. LTC,, LTD,, and LTE, comprise activity formerly referred to as "slow reacting substance of anaphylaxis." HPETE: hydroperoxy-eicosatetraenoic acid. and atelectasis which are the common, serious complications of asthma. 'I Excellent, detailed discussions of the immunology and biochemistry of asthma are available. 5J'2-'5 Intrinsic asthma is defined as reversible bronchospasm due to non-allergenic causes.2-4 Many different drugs (Table l) , such as aspirin (2% to 10% of attacks] and other anti-inflammatory agents (cyclooxygenase inhibitors), analgesics, and yellow dyes, especially tartrazines found in, for example, yellow gelatin and orange breakfast drinks, may cause bronchospasm. 16-19 The inhibition of cyclooxygenase by aspirin may cause more arachidonic acid to accumulate and more LTC,, LTD,, and LTE, to be produced, resulting in bronchospasm (see Figure 1 ). Vigorous exercise2' or emotional stress also may induce asthma.2i-26 Respiratory infections are frequent precipitants of asthmatic episodes (33% of acute asthmatic attacks) and are at least as frequent as exposure to allergens as a precipitating factor. 27 Viral ant1 bacterial respiratory infections seem to provoke instability of the airways non-specifically.2H~3' Also, cold weather as well as air pollution may induce bronchospasm.32t33 Body habitus may affect asthma, and some studies show that obese patients have an increased incidence of severe asthma and status asthmaticus.34t35 Therefore, in general there is a hyperreactivity to immunologic, emotional, infectious, or physical stimuli in asthma. The difference between extrinsic and intrinsic asthma plays no role in acute asthma in the emergency department and pulmonary function and response to bronchodilation is unaffected by this categorization of asthma. 36 The mechanisms behind extrinsic and intrinsic asthma involve a delicate balance between adrenergic and cholinergic systems and bronchial tone and are important in understanding the pathophysiology and therapy of acute asthma. Ahlquistj' developed the concept of (Y-and P-adrenergic receptors to explain the different effects of sympathomimetics at . JULY 1983 different sites. Lands et 01~s suggested that there were two forms of the P-receptor, PI and p2. When stimulated, the P1-receptors cause lipolysis and a chronotropit and inotropic effect on the heart. Beta2-receptors cause vasodilation, bronchodilation, skeletal muscle tremor, and muscle glycogenolysis. Alpha-receptors cause constriction of arteries, veins, bronchi, gastrointestinal and genitourinary sphincters, as well as hepatic glycogenolysis (Table 2) .39 More recently, 'or and %receptors have been described. The al-agonist, prototypically phenylephrine and methoxamine, cause smooth muscle contraction. The a2-agonist, prototypitally clonidine, inhibits the release of norepinephrine from the presynaptic nerve terminaL4' Stimulation of a-receptors may cause bronchoconstriction. Normal bronchi contain few a-receptors compared to the P-receptors, '3 but more a-receptors may be present in the bronchi of asthmatics4' Pate1 and Kerr48 and Snashall et ap9 have noted that in asthmatics the inhalation of a-agonists only in the presence of &blockade causes bronchoconstriction. This effect was not noted in nonasthmatic subjects. In asthmatics an a-adrenergic hyperresponsiveness has been noted in the pupils and vascular tone of patients with allergic asthma.50 The bronchoconstriction from a-agonists is enhanced several thousandfold in vitro by bacterial endotoxins5' and may mediate bronchospasm noted in bronchial infections. Alpha-adrenergic blocking drugs have been successful in the treatment of exercise-induced asthma.52g53 Bronchodilation is increased in asthmatics who received albuterol and (Yadrenergic blockers as compared to albuterol administered alone.54~55 In vitro a-agonists cause bronchoconstriction.5G-58 Alpha-receptor stimulation reduces CAMP production, increases the level of intracellular calcium and therebv causes smooth muscle contractions.59 ' Cyclic guanosine monophosphate (cGMP) is another intracellular second messenger whose formation is stimulated by cholinergic, parasympathomimetic agents, and which causes bronchoconstriction." Cholinergic stimulation may be responsible for cold or emotionally-induced asthma.'l Atropine may inhibit bronchoconstriction due to dust,G2 histamine,G3 and allergens.G4 Exercise-induced asthma may be inhibited by atropine if the main site of airflow obstruction is in the large airways.G51GG In summary, p-stimulation mediates broochodilation. In certain circumstances, cu-stimulation and parasympathomimetic agonists may mediate bronchoconstriction. In the last 15 years, much evidence has accumu-lated implicating a /3-adrenergic defect or epinephrine-resistance in the pathogenesis of severe asthma, and status asthmaticus has been defined by some as an unresponsiveness to epinephrine." This P-adrenergic defect may be involved in the development of an asthma attack. Aminophylline may result in an excellent response in status asthmaticus,68-70 as this drug bypasses the biochemical site of the putative adrenergic defect by inhibiting the enzyme phosphodiesterase (EC 3.1.4.1) causing an accumulation of CAMP (see Figure 2 ). In asthmatics, markedly impaired pulmonary,'l hematologic,72174 and metabolic74-76 responses to epinephrine are observed, thereby documenting this padrenergic defect. Most impressive is that these impaired responses to epinephrine correlate with the severity of the acute asthma.74~77-79 These defects return to normal once the patient is in remission!2t80f81 A similar adrenergic defect can be observed in patients with pheochromocytoma.82 Defects in the chronotropic and inotropic actions of /3-adrenergic agonists in asthmatics have not been consistently demonstrated, however.83t84 This P-adrenergic defect has been demonstrated on leukocytes of asthmatic subjects and in vivo in canine and human subjects,85-87 and, in part, may be due to chronic administration of turbutaline," albuterol, or isoproterenol.89g90 The defect has been well-documented, however, in chronic extrinsic asthma in patients not receiving any medications for asthma.91 The use of P-blockers in patients with sub-clinical asthma may precipitate cough, dyspnea, or bronchospasm. 92 In patients with known asthma, pblockers may increase the frequency or severity of attacks. Cholinergic stimulation also can cause bronchospasm, for example, during the diagnostic use of physostigmine for overdoses or treatment of acute myasthenia gravis with neostigmine or edrophonium.93 JOURNAL OF EMERGENCY MEDICINE l VOL 1 l JULY 1983 of a patient presenting for emergency care must be brief and oriented to his chief complaints and immediate therapy. In the asthmatic, it is important to elucidate precipitating factors such as drugs, allergens, and infectious causes of asthma associated with fever, chills, and productive cough. A thorough knowledge of the patient's present medications, current compliance, and last dosages is essential. in the past year should be elicited. Since wheezing may be minimal, it is important to recognize that exertional dyspnea and cough may be the only early manifestations of an asthmatic episode. 94195 In the initial evaluation of these patients one must consider other etiologies for wheezing, such as cardiac asthma and pulmonary embolism, as will be discussed later. The time of onset of a given attack is relevant96 as well as previous history of severe attacks and endotracheal intubation which tend to recur. 97 A patient should compare the severity of his present attack to other attacks that he has had: Is this his worst attack? ( Table 4) In large studies on acute asthma, respiratory rates range from 18 to 50 (mean of 31) and sinus rhythms varied in rate from 64/min to 150/min (mean of 100 f 6 [SEI).98t99 Pulse rates greater than 130/min are associated with severe respiratory distress and marked hypoxemia.68~98 Of patients with in-hospital complications of asthma, 75% had pulse rates greater than 130/min in the emergency department, as compared to only 5% incidence of complications if the initial pulse rate was less than 130/min.100 Approximately 40% of asthmatic patients have an elevated p&us paradoxus, that is, a decrease in systolic blood pressure with inspiration that may range from 15 mm Hg to 130 mm Hg. lo1 Pulsus paradoxus is caused by severe hyperinflation of the lungs with mediastinal and pericardial stretching combined with wide variations in intrapulmonary pressure"' and normally is less than 10 mm Hg. Pulsus paradoxus, if greater than or equal to 15 mm Hg, correlates well with a one-second forced expiratory velocity (FEV,) of less than 0.9 liters.102~103 In one study, one-third of patients who presented to the emergency department with pulsus paradoxus of greater than or equal to 15 mm Hg did not respond sufficiently to therapy over 12 hours and were admitted to the hospital. Those with an initial elevated pulsus paradoxus that decreased their pulsus paradoxus by only 20% were admitted to the hospital, whereas those discharged from the emergency department decreased their pulsus paradoxus by 60%. lo4 Clinical hyperinflation of the chest indicates at least moderate asthma105t106 and is due to persistent intercostal and accessory muscle contraction during expiration.lo7 Hyperinflation changes quickly with improvement or exacerbation. Persistence of hyperinflation may indicate that improvement will be brief. McFadden et aI"* carefully studied 22 patients with acute bronchial asthma and noted that retraction of the sternocleidomastoid muscle correlated well with the degree of mechanical impairment of the lung, usually with an FEV, of less than 1 liter. The presence of dyspnea, subjective wheezing, and expiratory wheezing was uniformly associated with airway obstruction, but the extent of obstruction could not be determined from these findings with any degree of precision. In fact, while 90% of patients became asymptomatic, 40% were still wheezing. In evaluating 127 emergency department visits by acute asthmatics, Kelsen et cd'09 found that pulsus paradoxus and sternocleidomastoid retraction occurred in 30% and 40% of episodes respectively and were more common than hypoxemia (~0, < 60 mm Hg) or hypercapnia (pC0, > 45 mm Hg) which occurred in 20% and 10% of episodes respectively. As the severity of the obstruction increased, the incidence of these findings increased; at an FEV, of less than 1000 ml, pulsus paradoxus and sternocleidomastoid retraction occurred in 50% of cases, whereas hypoxemia and hypercarbia were present in 35% and 15% of episodes respectively. An important implication of these findings is that pulsus paradoxus and sternocleidomastoid retraction may signify possible hypoxemia or hypercarbia and reflect the severity of bronchospasm. On auscultation of the chest, inspiratory wheezing indicates large airways are narrowed, and expiratory wheezing means smaller airways are narrowed. Inspiratory wheezing also may be due to tumor, foreign body, bronchitis, or misdiagnosed stridor. Findings which signify the most severe airway obstruction are mild intensity, high-pitched inspiratory wheezes without expiratory wheezing with the patient making grand efforts to breathe with minimal chest wall movement. When these signs are present, the patient is described as being "tight." An urgent finding is the "silent chest," indicating such severe obstruction that flow rates are too low to generate breath sounds. With improvement, wheezing may increase in intensity and become low pitched and coarse as flow rates increase.llO~lll Kales are often impossible to hear in asthmatics, because wheezing obscures these sounds. Also on physical examination the physician should check for subcutaneous emphysema or the presence of a mediastinal crunch (Hamman's sign). Fischl et LJ~"~ have developed an index scoring system to assess the severity of acute asthma. In this index, values of 1 are tabulated for pulse rate greater than or equal to 120, respiratory rate greater than or equal to 30, pulsus paradoxus greater than or equal to 18 mm Hg, peak expiratory flow rate (PEFR) less than or equal to 120 liters/min, dyspnea of moderate severity or greater, accessory muscle use of moderate degree or greater and wheezing which is of moderate severity or worse. The maximal possible score is 7. Scores of 4 or higher are 95% accurate in predicting risk of relapse within 10 days in patients discharged from the emergency department, and 96% accurate in predicting the need for hospitalization after 12 hours or less of emergency care. Only 3.3% of patients with a Fischl index of less than 4 required hospitalization. In a study of 49 adult patients, Brenner et a1113 showed that pulse rate, respiratory rate and pulsus paradoxus were significantly higher in patients initially assuming the upright, sitting position on admission to the emergency department; arterial pH, PO,, and PEFR were significantly lower in the upright patients, All upright patients had sternocleidomastoid retraction. Peak expiratory flow rate (PEFR) was 73.3 liter/min (* 5) in diaphoretic patients, 134 liters/min (+ 21) in non-diaphoretic, upright patients, and 225 liters/min (f 7.5) in recumbent patients (p < 0.02). No recumbent, non-diaphoretic patient had a PEFR less than 150 liters/min or pC0, more than 44 mm Hg. In 70% of upright patients and in 88% of diaphoretic patients the index of Fischl was 4 or higher, signifying a need for admission to the hospital. Only 7% of recumbent patients had Fischl indices of more than 4. Therefore, the position of a patient in the emergency department and the presence or absence of diaphoresis forms a continuum in severity in the initial assessment of acute asthma with recumbency without diaphoresis being the mildest form, upright without diaphoresis being more severe, upright and diaphoretic being most severe. As is well-known among clinicians and typified by one patient in this study, recumbent, diaphoretic patients have the most severe bronchospasm and frequently hypoventilate requiring mechanical assistance to breathe. The most ominous physical findings in acute asthma are those signifying hypoxemia or hypercarbia. Although agitation may be observed in as many as half of patients with asthma, agitation severe enough to halt speech is a sign of severe respiratory distress. In most patients with asthma so severe that they are unable to speak, the p0, is less than 40 mm Hg; in some cases thought to be mild, however, the p0, is as low as 45 mm Hg.98 Physical signs of hypoxia are not observed until hypoxemia is severe. These signs are restlessness, faintness, pallor, and diminished ability to discriminate which occur at arterial oxygen saturations of less than 75%.114,'15 Immediately before unconsciousness due to anoxia, motion of the face and upper body decreases suddenly and the patient seems to be staring. There is amnesia for events preceding the arrest.' l6 During hypoxia, hyperventilation, hyperpnea AMERICAN IOURNAL OF EMERGENCY MEDZClNE l VOL 1 l Lucy 1983 and tachycardia occur115~117~118 which develop while patients breathe room air, but not while ventilation is controlled or while hypocarbia is prevented with a COz-enriched atmosphere.'14 p0, of more than 40 mm Hg protects against tissue hypoxia and lactic acidosis. '14 In asthmatics, an important reflection of severe hypoxemia is cyanosis. Cyanosis is due to presence of unreduced hemoglobin in dermal papillae and subpapillary venous plexi of the dermis.' lo Based on studies of venous blood, Lundsgaard1191120 showed that 4.5 g to 5.2 g of reduced hemoglobin is needed to exceed the threshold for observing cyanosis. Later Geraci and Wood121 pointed out that only 3.3 g of reduced hemoglobin was needed to observe cyanosis in white patients. Polycythemia, by providing more hemoglobin for reduction and acidosis by shifting the hemoglobinoxygen dissociation curve to the left, encourages increased amounts of unreduced hemoglobin and, therefore, enhances the development of cyanosis. Alkalosis will shift the hemoglobin-oxygen dissociation curve to the right, prevent the release of oxygen from hemoglobin, and decrease the amount of reduced hemoglobin. If anemia is so profound that insufficient reduced hemoglobin is present to generate cyanosis, then anemia will prevent the appearance of cyanosis despite severe hypoxemia. When cyanosis is present, it is important to decide whether it is peripheral or central. Peripheral cyanosis involves the extremities such as nail beds, ear lobes, and nose and is caused by slow circulation during 1) hypoperfusion (e.g., shock, congestive heart failure, Raynaud's phenomenon), or 21 stasis (e.g., polycythemia, superior vena cava obstruction, or venous thrombosis). 122 If cyanosis is central (diffuse pattern involving lips, tongue, buccal mucosa) the causes are 1) right to left shunt (e.g., pulmonary arteriovenous anomaly, tetralogy of Fallot); 2) pulmonary disease (e.g., pneumonia, pulmonary edema, asthma); 3) lowinspired oxygen (e.g., high altitudes); 41 abnormal hemoglobin (e.g., methemoglobin 11.5 g causes cyanosis] or sulfhemoglobin lo.5 g causes cyanosis]); 61 polycythemia; and 7) acidosis.119,123 Intermediate between peripheral and central cyanosis is differential cyanosis in which only certain regions, such as the upper half of the body, appear cyanotic as occurs in patent ductus arteriosus, transposition of the great vessels, or coarctation of the aorta. Cyanosis is unreliable in detecting mild to moderate hypoxemia. In over 3500 observations in white patients made by 12 physicians on staff and 12 medical 56 students, Comroe and Botelho124 noted considerable interobserver variability in the appreciation of cyanosis. Three percent of observers did not note cyanosis when arterial oxygen saturation was 71% to 75%, 10% did not note cyanosis when arterial oxygen saturation was 76% to 80%, and 14% did not note cyanosis when saturation was 80% to 84%. Twentyfive percent of observers noted "slight cyanosis" despite arterial oxygen saturations of 96% to 100%. This study showed that most cases of cyanosis (85%) could be diagnosed when arterial oxygen saturation was less than 85%; however, there is a high incidence of false positives. Geraci and Wood12' asked observers to evaluate the degree of cyanosis in 1803 white patients. They felt that patients had no cyanosis with arterial saturation averaging 90% (range 69% to 95%), had questionable slight cyanosis at average arterial saturation of 84% (range 69% to 95%), had definite slight cyanosis at average arterial saturation of 80% (range 62% to 95%), and severe cyanosis at arterial saturation of 67% (56% to 76% range]. Although there was marked overlap of the ranges, there is a rough correlation between the degree of cyanosis and arterial oxygen saturation. In the same study, in 450 observations in black patients, the threshold of arterial oxygen saturation for the appreciation of cyanosis was 3% to 8% lower than for whites; no black patients were observed with severe cyanosis. Geraci and Wood concurred with Comroe and Botelho that definite cyanosis was seen by all observers if arterial oxygen saturation was less than 75%, but most observers noted cyanosis at less than 85% saturation.12' J124S'25 For observing cyanosis, the choice of site affects the percent of observers feeling that a particular region is cyanotic. The presence of cyanosis may be affected by vascularity, pigmentation, and thickness of the skin.' " Lips, tongue, and buccal mucosa are highly reliable sites for the detection of central cyanosis but have a 40% incidence of false positives in one series. If these areas are not cyanotic, then it would be rare for arterial oxygen saturation to be less than 75%!2"~'27 Conjunctivae, ear lobes, and nail beds were poor sites to observe central cyanosis, because these regions were prone to hypoperfusion. 12 ' Bright light is inferior to normal light in the diagnosis of cyanosis. In studies excluding black patients, 97.5% of observers noted slight cyanosis at less than 90% arterial oxygen saturation, when viewed in certain fluorescent lighting.12 ' In a similar study comparing fluorescent lighting to tungsten, only 50% of observers noted cyanosis at 85% to 89% arterial oxygen saturation with fluorescent lighting. No superiority of tungsten over fluorescent lighting was noted.lz8 In acute asthma, respiratory failure and hypercarbia may occur and are important to diagnose early. The physical findings of hypercarbia are diaphoresis secondary to increased cutaneous blood flo~,"~-~~' increased cardiac output, 471131~132 hyperdynamic cardiovascular system with wide pulse pressure (up to a pC0, of 90 mm Hg),1321133 elevated blood pressure 130-'32 and depression of central nervous system.'13' These findings suggest hypercarbia before the results of the arterial blood gas are known. Before obtaining the results of arterial blood gases, meaningful information can be obtained from the color of the arterial biood. Morgan-Hughes and Bartlett'34 compared arterial samples with standard samples saturated with oxygen by shaking them for five minutes with oxygen. All observers noted that blood with less than 85% saturation was darker than the saturated blood. Eighty percent of observers noted that blood with arterial oxygen saturation of 85% to 90% was darker than fully saturated blood, and at 90% to 94% oxygen saturation, 70% of observers noted that the sample was darker than the standard. If hemoglobin was less than 10 g, then all observers detected which samples were darker at less than 95% arterial oxygen saturation. This technique is superior to observations of cyanosis in not being masked by overlying skin pigmentation, ease of controlling lighting conditions, and ease of recognition despite anemia. Before therapy, laboratory studies may include complete blood count (CBC) with differential, cold agglutinins, sputum examination and, if available, aminophylline level and total eosinophil counts. (The rationale for each individual test will be discussed later in this section.) Baseline PEFR or FEV, should be measured, if these are available, and the patient is not too agitated. Measurement of arterial blood gases is crucial to guiding therapy in the absence of direct flow measurements; but providing oxygen for an agitated patient in obvious respiratory failure is more important than spending many minutes attempting to obtain an arterial blood gas. A clinically mild asthmatic need not undergo any blood tests, but the measurement of flow rates is inexpensive, non-invasive, can be repeated frequently, and is of value in all asthmatic patients. Specific Laboratory Tests (Table 51 During the asthma attack the white blood cell count is elevated in one half of cases with a range of 6.1 to 28,000 (mean 14.9). The percentage of neutrophils is 46 to 96 (mean 76.5) and is raised in over one' third of cases; the percentage of eosinophils is raised in one third of cases ranging from 0 to 36 (mean 5). The erythrocyte sedimentation rate is elevated in one third of cases, but the average rate is normal (mean 13).98 Hematocrit rises 7% during the asthmatic attack and serum proteins increase by 0.6 g per 100 m1.145 Unnecessary if PEFR is above 130/min or more than 25% of predicted, or patient is recumbent and nondiaphoretic. Petients not receivmg artend blood gnses should receive supplemental oxygen. 6. Sputum examination Mild asthmatics may not need any blood examinations. The normal total eosinophil count is 122 (+ 74 [SD]). In steriod treated asthmatics in remission, the total eosinophil count is less than 85. In one study every patient with acute asthma had a total eosinophil count of more than 350, if not on steroids, or greater than 85 if the patient was on steroids. The total eosinophil count also correlated well with the FEV, and lung volumes146 and could be used to titrate the dose of steroids in asthmatics both in in-patient and outpatient settings; moreover, the total eosinophil count has been used even to anticipate an acute attack days to weeks prior to clinical exacerbation.J4' Expectorated sputum examination reveals white cells but no organisms in 95% to 97% of cases.27~98,103 In children, viral infections are associated with acute asthma in 26% to 42% of patients with most due to respiratory syncytial virus or rhinovirus (half of these were accompanied by pneumonia), followed by parainfluenza 2 and coronavirus infections.148~149 In adults, only 10% of asthmatic attacks have an associated respiratory infection of which half are bacterial pathogens (Staphylococcus aureus, Streptococcus pneumoniae and Hemophilus influenzael. 150-152 Cultures for aerobic and anaerobic bacteria, mycobacteria, fungi, mycoplasma, and viruses obtained by transtracheal aspiration did not distinguish between 27 adult asthmatic subjects and 12 volunteer controls. Therefore, routine use of antibiotics in all acute asthmatics seems excessive!53g154 However, the judicious use of prophylactic penicillin or sulfonamides during winter months may decrease asthma and respiratory infections in children. 155 A sputum examination is adequate if less than 10 squamous cells are present per low power field in the sample. ' 56 Sputum can be examined unstained for the presence of eosinophils,15' Charcot-Leyden crystals (condensation of secretions of eosinophils),158~159 Curshman spirals composed of mucus, debris from leukocytes and bronchiolar cells,15' and Creola bodies consisting of clusters of bronchiolar cells.160~161 Although sputum eosinophilia may occur in asthma, much sputum eosinophilia also may be seen in chronic bronchitis. 162 Another bedside test, determination of cold agglutination"'* may be a helpful guide to antibiotic ther- ' For the rapid assessment of cold agglutination, place approximately 0.2 ml blood in a tube containing sodium citrate solution ("Blue Top Tube" Becton-Dickinson, Rutherford, NJ) and place the tube in an ice water mixture. After five minutes, tilt the tube. In a positive test, the observer will see floccular agglutination."' 58 apy. ' It is important to note that it takes five to seven days to develop significant titers during Mycoplasma pneumoniae infections, and the elevated titer persists for more than 30 days after infection.169f1170 Aminophylline levels are most useful in managing acute asthma. The initial level often provides information about patient compliance and the efficacy of a given outpatient regimen of aminophylline. Furthermore, there are wide interpatient differences in elimination rate, so that the dose of the maintenance infusion frequently must be monitored by aminophylline levels to insure therapeutic effectiveness. Many assay systems exist; a new interesting enzyme immunoassay is reliable, quick, and simple172 (see Aminophylline in Part 2 of this article). Testing arterial blood gases of acute asthmatics provides important information. These Simple or mixed metabolic acidosis has been reported in 38% of acute asthmatic patients admitted to an intensive care unit. 174 Metabolic acidosis is seen frequently in children with acute asthma."" In the study by McFadden and Lyons, mild obstruction was defined as FEV, of above 50% of predicted and was associated with a mean p0 of 83 mm Hg (+ 11 [SD] ] and pC0, of 25 mm Hg !k 4 [SD]]; moderate obstruction was defined as FEV, below 50% but more than 25% and was associated with a p0, of 71 mm Hg (* 9 [SD]) and pC0, of 33 mm Hg (+-4 [SD]); and severe obstruction was defined as FEV, below 25% and was associated with a mean p0, of 63 mm Hg jf 9 [SD]) and pC0, of 39 mm Hg (* 7 [SD] A normal pC0, may be ominous in status asthmaticus. Rebuck et up8 noted a rough correlation between pC0, and FEV, (r=O.66). Fifteen percent of their patients had evidence of hypercarbia with pC0, above 60 mm Hg in 4%. Hypercarbia also was more common in those with reduced FEV,, but even in those with FEV, of less than 0.75 liters, the range of pC0, was 27 mm Hg to 75 mm Hg. Severe hypercarbia is often (60%) associated with underestimation of the severity of asthma and inadequate initial treatment by physicians, as manifested by the omission of corticosteroid therapy or a loading dose of theophyllines or by the use of sedatives or anti-tussives. Patients or parents of patients frequently underestimate the severity of asthma resulting in serious delays in seeking emergency care. 18' Pneumothorax, or more commonly pneumomediastinum or pneumonia, may contribute to hypercarbia and severe asthma103~182 (see Acute Respiratory Failure in Part 2 of this article). In comparing patients requiring more than 24 hours of therapy (slow responders) to patients requiring less than 24 hours of therapy (rapid responders), initial pC0, and PEFR were more aberrant in the slow responders. Most significant was that slow responders, a group which required admission to the hospital for prolonged therapy, could be readily distinguished from the rapid responders; the slow responders had a less than 30% improvement in PEFR during the initial four hours of therapy, whereas the rapid responders developed a more than 70% improvement from initial PEFR during this four-hour period." ' Although more expensive than PEFR, FEV, measurements are also useful but no more superior than PEFR.189 In 25 severe patients FEV, had been shown to vary from 0 liters to 1.25 liters on presentation (mean of 1.54 liters) with a mean forced vital capacity (FVCl of 1 liter (range 0.7 liters to 1.85 liters), both less than 25% of predicted. Percent FEV,/FVC was 44% (25% to G6%), which was 50% of predicted. These patients were frequently severely distressed or exhausted at presentation; some were too ill to perform an FEVi.981103 Patients with less severe asthma without exhaustion or altered consciousness showed an FEV, from 0.25 liters to 2 liters with a mean of 0.8; whereas those with mild asthma had mean FEV, of 1.2 liters (0.4 to 3.05 range]. As can be seen, there was a general correlation between FEV, and estimates of clinical severity, but much overlap in the rangeslo The value of the FEV,, as compared to other clinical measures, was emphasized by Kelsen et al."9 Their patients were evaluated by house officers in the emergency area and discharged when the patients were asymptomatic and wheeze-free. On admission and discharge from the emergency department, FEV, was measured, but these values were unavailable to the house officers. Kelsen and colleagues showed that clinical signs of improvement (asymptomatic, "clear chest") correlate poorly with FEV, in acute asthmatics and have a high incidence of "false negative" results. As noted earlier, sternocleidomastoid retraction was lacking in 50% of their patients with severe obstruction. The authors showed that substantial airway dysfunction was still present at the time of discharge from the emergency department in asymptomatic, wheezefree patients. Mean initial FEV, of discharged patients was 1,149 as compared to 1,767 for the FEV, at the time of discharge from the emergency area (only 60% of predicted normal value). Eight percent of discharged patients had no improvement in FEV, at all, but allegedly had improved sufficiently to warrant discharge. Patients who returned to the emergency department differed from those without relapse in having a FEV, at discharge of 1563 ml (f 108 [SE] ) and FEV, of 1879 ml (-t-110 [SE]) respectively. A change in FEV, during the stay in the emergency department of 400 ml or below resulted in two thirds of these 60 patients returning to the emergency department. Therefore, the customary ending of treatment in the emergency department (wheeze-free and asymptomatic) seriously underestimates the severity of acute asthma. Direct flow measurements provide a better assessment of the severity of asthma than clinical evaluation. Nowak et 01'~" carefully studied by spirometry 85 patients with asthma seen in emergency departments and followed these patients even if sent home. The results of their spirometric evaluations were unavailable to the physicians deciding whether to admit the asthmatic to the hospital. Patients who were sent home, yet persisted in having marked respiratory symptoms, were regarded by the authors to have been wrongly discharged from the emergency department and should have been admitted to the hospital. They noted retrospectively several spirometric criteria for admitting patients with asthma to the hospital, 1) illness too critical to perform spirometry (3 patients) j 2) an FEV, of below 0.6 liters or an initial improvement of only 0.15 liters or less after subcutaneous injection of epinephrine or terbutaline (45 patients fell into this category of whom 36 initially required admission to the hospital or developed marked respiratory symptoms after discharge. Most patients improved 260 ml to 570 ml in FEV, 15 minutes after the subcutaneous injections]; and 3) an FEV, of below 1.6 liters at the end of therapy (51 patients were in this category with 38 initially requiring admission to the hospital or developing marked respiratory symptoms after discharge). Moreover, 90% of patients with FEV, below 0.6 liters at initial measurement and FEV, below I.6 liters at the end of therapy were either admitted or developed pulmonary problems after discharge and should have been admitted initially. In another study by Nowak et ~1'"" patients who had a pre-therapy PEFR of less than 100 liters/min and received 0.25 mg terbutaline, but were below 160 liters/min post-treatment, had an 85% chance of admission or a poor out-patient course. Those patients whose pre-treatment PEFR was below 100 liters/min and had a PEFR of below 300 liters/min after their entire emergency treatment had a 92% chance of admission or poor out-patient course. When the ratio of physiologic dead space-to-tidal volume (VI/VT) was measured in 51 adults with acute bronchial asthma, the ratio was elevated in all patients (mean 0.5 f 0.06 (SD]; normal value 0.25 to 0.35). This finding reflects an increased physiologic dead space in acute asthma."s This ratio, if over 0.6, sensitively indicates severe respiratory failure and the need for endotracheal intubation and assisted ventilation.lgl The V,,/VT ratio can be measured rapidly in asthmatics by measuring the expired tidal volume (EVT) with a spirometer, respiratory rate (RR), the expected minute ventilation IV,) obtained from a standard nomogram, 192 and the pC02 by using either of the following formulae!78~193~194 The first formula may vary 10% more or less but is easier to remember. The second formula is more accurate. ( Table 7) In evaluating a patient with acute asthma, a chest radiograph is important because physical findings of asthma frequently obscure other pulmonary abnormalities. Radiographic hyperinflation is the most common finding (45%) but correlates inconsistently with clinical severity.98~195~196 S tattered atelectatic opacities consistent with mucus plugging of bronchi occur in 15% of cases.lo3 Pneumothorax or pneumomediastinum may be found 197-202 and are often clinically unsuspected in up to 10% of patients. lo3 Pneumothorax or pneumomediastinum is usually small and resorbs at 1.25%/day with high flow oxygen. Tension pneumothorax or a pneumothorax of greater than 20% should be treated by the insertion of a chest tube. Rarely a tension pneumomediastinum may develop requiring incision into the mediastinum at the suprasternal notch to prevent circulatory embarrass-ment203 JO4 Both benign and tension pneumopericardium have been described in acute asthmatics 205,206 In asthmatic patients with respiratory failure lpC0, 5 45 mm Hg, pH s 7.3), P pulmonale was found in 50% as compared to 2.5% of acute asthmatics not in respiratory failure.211 In a careful study of 63 asthmatics, Siegler212 found the most common electrocardiographic abnormality in 78% of patients to be a vertical P wave axis, defined as a P wave greater in height in lead II and III than in lead I and negative in lead AvL. ST-T wave changes suggestive of myocardial ischemia have been noted.98,212 Although reversible, these ECG changes have not correlated well with the degree of pulmonary impairment during the acute attack or during remission. 213 Exacerbations of asthma at night are particularly worrisome. The risk of sudden death is increased and may be more related to excessive diurnal "dips" in PEFR in the early morning hours than to severity of the attack.214(215 The diurnal cycles are not prevented by resting in bed for 24 hours and cannot be attributed to an allergy to the house dust mite found in bedding. With a change to working night shifts, the diurnal pattern almost immediately shifts to the patient's new sleep hours, causing a dip in the PEFR in the mid-part of sleep, changing quicker than other physiologic measurements such as temperature or plasma cortisol level. It is concluded from these data that interruption in bronchodilator therapy during sleep hours may be an important factor.216 When the morning "dip" in cortisol is prevented by an infusion of physiologic doses of hydrocortisone, excessive diurnal variations in PEFR persist.217 During sleep deprivation some patients no longer have a nocturnal decrease in PEFR; in other patients, a sleep-dependent decrease in PEFR persists.21" Barnes et a12'" noted in five patients with extrinsic asthma that the nocturnal decrease in PEFR corresponded quite specifically to the time of sudden diurnal decrease in plasma epinephrine and CAMP level and sudden increase in serum histamine level. Therefore, it was suggested that endogenous epinephrine maintains bronchial tone through its pagonist effect or by preventing histamine release from the mast ce11~20~221 subsequently, bronchospasm would occur at the time of night when epinephrine level was depressed. Unlike inhaled histamine, intravenous histamine, however, does not cause much bronchospasm, and the level of plasma histamine may serve more as a marker for mast cell degranulation than as a direct indicator of bronchospasm.222 Other substances such as SRS-A released from mast cells may be more involved than histamine in the mechanism of bronchospasm in nocturnal asthma.223 Some episodes of nocturnal asthma may be due to decreases in aminophylline levels which occur during the night. Improvement in nocturnal asthma may occur with use of long-acting aminophylline preparations. 224 Other studies fail to confirm the value of long-acting bronchodilators in nocturnal asthma.22" Another possibility for the sleep-dependent nocturnal exacerbations of asthma is that with a heightened reactivity of the bronchi to different stimuli in asthma, these patients may wheeze in response to small amounts of aspiration that occur during s1eep.22"J227 Mays22R noted that 60% of 28 severe asthmatics had hiatal hernia and 500/o had esophageal reflux as compared to 20% and 5% respectively of almost 500 matched control patients. Older asthmatics and those with predominantly nocturnal episodes seemed predisposed. Only 50% of asthmatics with reflux had gastrointestinal symptoms. In part, this high incidence of reflux may be caused by use of aminophylline which reduces lower esophageal sphincter pressure. 229,230 Similar findings have been reported in the surgical literature in patients who develop asthma late in life and 90% cure rates are reported after surgical repair of reflux.2311232 Mays22" and more recently Goodall et al 233 have reported that intensive antacid and anti-reflux therapy was successful in his experience in treating such asthmatics. Others have found antacids and anti-reflux positions to be ineffective in asthma.234 Differential Diagnosis (Table 9) The diagnosis of asthma clearly is not difficult in patients with a long history of reversible bronchospasm who present with an attack. Patients who are too short of breath to give a history or those with their first episode of asthma may present a difficult diag-62 nostic problem. Other entities may masquerade as asthma, and one must remember that "all that wheezes is not asthma!"235 In pediatrics, asthma is not diagnosed with confidence until the child is more than three years o1d.236a237 Asthma may be suspected at earlier ages after multiple episodes of bronchiolitis with wheezing which has been reversed by bronchodilators. Cardiac asthma (defined as congestive heart failure with wheezing as the predominant manifesta-tion1238r239 and chronic obstructive pulmonary disease (COPD) with exacerbation must be distinguished from bronchial asthma. In both cardiac asthma and COPD with exacerbation, epinephrine should not be used. In cardiac asthma, rapid hydration is contraindicated, and in COPD with exacerbation, high-flow oxygen by nasal cannula may be deleterious. When these patients present in extremis, rapid physical examination, laboratory studies, and chest roentgenograms must be relied on for diagnosis. Major findings in COPD with exacerbation and cardiac asthma are signs of right-sided heart failure, an older age of onset of symptoms, peripheral edema, and hepatojugular reflux. Cardiac asthma is favored by an absence of leukocytes in sputum, left ventricular hypertrophy on ECG and chest radiograph. Auscultatory findings other than very loud murmurs are usually obscured by wheezing. Cardiac asthma in a young patient may be due to occult mitral stenosis. COPD with exacerbation is favored by the history of smoking for many years, barrel-chest or body habitus of the pink-puffer or blue-bloater, clubbing of the nail beds, an elevated hematocrit, car pulmonale on ECG, marked hyperlucent lung fields, flattened diaphragms, intrinsic lung disease on chest radiograph, and blood gases showing chronic hypercarbia. In patients presenting with asthma, pulmonary infiltrates, and peripheral eosinophilia of more than lo%, several major diagnostic possibilities must be considered. Allergic bronchopulmonary aspergillosis may present as this triad. In this disorder, aspergillus precipitins, positive aspergillus skin tests, and elevated IgE levels may be found.240~241 IgE levels vary with severity and elevations may even precede clinical complaints.242 These patients should be treated with moderate doses of steroids, for as little as 60 mg of prednisone/day may cause tissue invasion by the organism.243 Loeffler's syndrome is another possible diagnosis for this triad. In this disorder, pulmonary infiltrates with eosinophilia (PIE syndrome) results in minimal symptomatology. The syndrome lasts less than six weeks. Chronic eosinophilic pneumonia also may present as asthma classically in middle-aged women with chronic pulmonary infiltrates simulating the photographic negative of pulmonary edema,244 peripheral eosinophilia and marked constitutional symptoms. 245 These patients respond dramatically to It is important to identify occupation-related exposures to allergens as such because they can be prevented. Offending agents include cotton fibers in byssinosis, actinomyces spores in farmer's lung, chemicals such as toluene diisocyanate, and metal fumes. Syndromes of chest tightness, dyspnea, and fever are characteristic. The key to diagnosis is that symptoms begin late in afternoons, are worse at night, and improve on awakening, weekends, and holidays.248-253 Symptoms are worst on Monday and improve progressively by Friday. Colophony fumes (released during soldering) produce bronchospasm which becomes progressively worse during the week.254 Other considerations not difficult to distinguish from bronchial asthma are acute chemical injury of the lungs by such agents as ammonia or sulfur dioxide,255 by smoke inhalation, in which carbon monoxide levels are elevated and carbonaecous sputum and singed nasal hairs are present.256-259 Other causes of non-cardiogenic pulmonary edema with marked or rapidly progressive pulmonary infiltration must be considered. Viral or bacterial pneumonia may precipitate or simulate asthma, but radiographic and sputum findings usually provide rapid distinction. Upper airway obstruction can be rapidly fatal and should never be overlooked. In Carcinoid syndrome is associated with wheezing in 20% to 30% of cases. Flushing, frequently postprandial, and a murmur of tricuspid stenosis or insufficiency may suggest this diagnosis. Nausea, vomiting, and often explosive diarrhea may also be present.278 Invasive phases of worm infestation may mimic a first bout of bronchial asthma. Hookworm, Strongyloides, and Ascaris, which infect 25% of the world's population, are associated with bronchospasm, fever, and eosinophilia 4 to 16 days after inoculation. The diagnosis may be made definitively by detecting the larvae in sputum.279-285 In allergic angiitis, described by Churg and Strauss,286 and other types of vasculitis, patients may present with intractable bronchial asthma and marked peripheral eosinophilia. Upper respiratory symptoms and abnormalities on chest roentgenograms are frequent. Subsequent development of polyarteritis nodosa or vasculitis in other organs and rapid clinical deterioration are diagnostic; in patients with vasculitis, respiratory disease accounts for 50% of the deaths2""-290 Lastly, an atopic or non-atopic patient may have an isolated or discrete episode of severe bronchospasm secondary to exposure to a known or unknown allergen. Anaphylaxis with shock and giant urticaria may occur and is the hallmark of this entity. Monitoring serum theophylline levels Arterial blood-gas tension in asthma Metabolic acliosis in status asthmaticus Artertal blood gas ten-