553CHAPTER 50 Asthma who died of asthma were judged to have a history of trivial or mild asthma, whereas 32% had never been admitted to the hos pital with an asthma exacerbation 5 More recently, the C[.]
CHAPTER 50 Asthma • BOX 50.1 Risk Factors for Near-Fatal Asthma Medical Factors Previous asthma attack with: • Admission to intensive care unit • Respiratory failure and mechanical ventilation • Seizures or syncope • Paco2 45 torr • High consumption (.2 canisters per month) of b-agonist metered-dose inhalers • Underuse of corticosteroid therapy Psychosocial Factors • • • • • Denial of or failure to perceive severity of illness Associated depression or other psychiatric disorder Noncompliance Dysfunctional family unit Inner-city resident Ethnic Factors • Nonwhite children (black, Hispanic, other) Intubation may occur prior to PICU admission and is associated with shorter duration of mechanical ventilation.20 Despite this increase in critical care utilization, mortality rates from acute severe asthma (,0.1%), critical asthma (,0.3%), and nearfatal asthma (,4%) are quite low Many of the deaths from asthma occur in patients who experienced prehospital cardiac arrest.8,16,18,20 Risk factors for severe asthma exacerbations are of particular importance to the practicing intensivist (Box 50.1) Critical asthma is disproportionately more common in boys, impoverished regions, Hispanic children, and African-Americans.9,20 Risk factors for near-fatal asthma include African-American race, older age, concurrent pneumonia, and the presence of comorbid conditions.8,14,18 The majority of patients with asthma who progress to nearfatal asthma or cardiac arrest so prior to arrival at the emergency department or during the first stages of therapy.8,22 Therefore, early identification and close monitoring of patients at high risk for near-fatal asthma could be advantageous High-risk patients often have a history of ICU admissions,23,24 mechanical ventilation,4,23 seizures or syncope during an attack,25 Paco2 greater than 45 torr,4,23 attacks precipitated by food,23 atopy,26 or a history of rapidly progressive and sudden respiratory deterioration.5 High-risk patients are likely to use more than two canisters of b-agonist metered-dose inhalers per month27 and often are poorly compliant or are receiving insufficient steroid therapy.28,29 Denial or imperception of the severity of an attack are factors frequently associated with near-fatal asthma.30,31 Although, unquestionably, some patients at risk for near-fatal asthma simply ignore early warning signs and not seek medical attention, a subgroup of patients actually lacks normal perception of disease severity Some patients with nearfatal asthma exhibit reduced chemosensitivity to hypoxia and blunted perception of dyspnea.32 Other patients have a decreased perceptual sensitivity of inspiratory muscle loads and display abnormal respiratory-related evoked potentials.33 Although many of these high-risk factors are commonly present in patients with near-fatal asthma, they fail to identify a significant number of cases In one case series, 33% of patients 553 who died of asthma were judged to have a history of trivial or mild asthma, whereas 32% had never been admitted to the hospital with an asthma exacerbation.5 More recently, the Collaborative Pediatric Critical Care Research Network reported that 13% of 260 children with near-fatal asthma had no prior history of asthma and that only 37% of known asthmatics had required hospitalization in the 12 months preceding the episode of nearfatal asthma.8 Some of these patients may, in fact, have what likely represents a distinct clinical entity known as sudden asphyxial asthma, a condition marked by acute onset of severe airway obstruction and hypoxia that rapidly leads to cardiorespiratory arrest in patients known to have only mild asthma or no asthma history at all.34–36 Pathophysiology Asthma is primarily an inflammatory disease As such, it is marked by highly complex interactions among inflammatory cells, mediators, and the airway epithelium (Fig 50.1).37 Functionally, asthma is characterized by variable airflow obstruction and airway hyperresponsiveness associated with airway inflammation and may represent a spectrum of unique pathophysiologic phenotypes and endotypes.38 Though various phenotypes cause clinical asthma, asthmatic patients commonly have airway inflammation dominated by eosinophils, TH2 cytokines, and immunoglobulin E (IgE).39 Pathologically, it is marked by mast cell degranulation, accumulation of eosinophils and CD4 lymphocytes, hypersecretion of mucus, thickening of the subepithelial collagen layer, and smooth muscle hypertrophy and hyperplasia.40 Mast cells, eosinophils, neutrophils, macrophages, and T lymphocytes are central to the derangements that occur during an acute attack (see Fig 50.1) The usual cascade begins with the activation and degranulation of mast cells in response to allergens or topical insults Mast cells release mediators—including histamine, prostaglandins, and leukotrienes—that cause acute bronchoconstriction Additionally, the mast cells promote activation of T lymphocytes via allergen presentation The inflammatory process is then amplified by T-lymphocyte release of cytokines and chemokines, predominantly TH2 cytokines, such as interleukin (IL)-4, IL-5, IL-8, and IL-13.41 The presence of these TH2 cytokines leads to further augmentation of the inflammatory process through excessive production of IgE by B cells, stimulation of airway epithelial cells, and eosinophil chemotaxis IgE stimulates mast cells to release leukotrienes, whereas interleukins (particularly IL-5) promote maturation and migration of activated eosinophils into the airway.42 This highly inflammatory state results in stimulation of airway epithelial cells and continued augmentation of the inflammatory process by further release of leukotrienes, prostaglandins, nitric oxide (NO), adhesion molecules, and platelet-activating factor This process results in overproduction of mucus and in epithelial cell destruction that lead to airway plugging and denuding of the airway surface Disruption of the epithelial surface exposes nerve endings, resulting in hyperirritable airways43 that become more susceptible to spasm and obstruction when challenged by subsequent exposures to allergens and irritants.44 Airway irritants that trigger acute asthma include cigarette smoke and inhaled particulates,45 respiratory tract viruses,46 psychological stress,47 and cold air.48 The mucus secreted in the airways of asthmatics contains large amounts of cellular debris and is thicker than in normal persons.49 Mucus hypersecretion may be a principal cause of respiratory failure in persons with severe asthma and has been underappreciated as a factor in respiratory failure.49–51 554 S E C T I O N V Pediatric Critical Care: Pulmonary Antigen or topical insult Mast cell lgE B-cell Proinflammatory cytokines, IL-4 Macrophage T-cell NORMAL AIRWAY Chemokines IL-4 LTB-4 Histamine Leukotrienes Prostaglandins Neutrophil INFLAMMATION Mucosal edema Bronchospasm Mucos plugging IL-5 IL-5, IL-8, IL-13 Proinflammatory cytokines Eosinophil Macrophage Cytokines ACUTE ASTHMA AIRWAY • Fig 50.1 Cellular and humoral mediators that lead to mucosal edema, bronchospasm, and mucus plugging in patients with acute asthma IL, Interleukin; IgE, immunoglobulin E; LTB-4, leukotriene B-4 Ultimately, inflammation-mediated airway edema, mucus hypersecretion, airway plugging, and bronchospasm lead to the severe airway obstruction seen in patients with severe asthma exacerbations The resulting obstruction and increased airway resistance create an impediment for inspiratory and expiratory gas flow, which leads to deranged pulmonary mechanics and increased lung volumes.50 Airway plugging can result in ventilation/perfusion mismatching and an increased oxygen requirement Hypoxemia is nearly universal in patients with a severe asthma attack, but generally it is easily corrected with supplemental oxygen52 and is only weakly correlated with pulmonary function abnormalities.53 More frequently, heterogeneous airway plugging and obstruction lead to regional alveolar hyperinflation associated with reduced perfusion, resulting in a significantly increased pulmonary dead space Most patients with acute asthma exhibit an increased respiratory rate in an attempt to achieve a higher minute volume and compensate for the ventilation abnormality In asthmatics with acute exacerbations, airway obstruction results in significant prolongation of expiratory time The subsequent breath is initiated before the last one has emptied, leading to dynamic hyperinflation The small airways collapse and close at a higher than normal lung volume, contributing further to air trapping At higher lung volume, there is a higher alveolar driving pressure to empty the lung, which should serve as an adaptive mechanism However, the net result in acute asthma is high-energy use Expiration becomes active with the use of the abdominal muscles At high lung volumes, the lung is less compliant and the inspiratory accessory muscles are engaged to help move an adequate tidal volume.54,55 During a severe attack, inspiratory transpulmonary pressures in excess of 50 cm H2O may be generated compared with approximately cm H2O during normal breathing.56 The increased CHAPTER 50 Asthma muscle work is accompanied by an increase in blood flow to the diaphragm, but this flow often is insufficient to meet the much greater metabolic demands.57 Failure to promptly relieve the airway obstruction and reduce the work of breathing eventually lead to respiratory muscle fatigue, inadequate ventilation, and respiratory failure States of advanced airway obstruction and dynamic hyperinflation typical of severe asthma attacks have a significant impact on the circulatory system The highly negative intrapleural pressures generated by spontaneously breathing patients during inspiration favor transcapillary fluid movement into the interstitium and air spaces, promoting pulmonary edema.55 They also cause a phasic increase in left ventricular afterload and a decrease in cardiac output58 that is clinically manifested as pulsus paradoxus.59 Right ventricular afterload may be increased during severe asthma because of pulmonary vasoconstriction related to hypoxia and acidosis A state of increased pulmonary vascular resistance resulting from dynamic hyperinflation also can increase right ventricular afterload, further affecting cardiac output.59–61 Clinical Assessment 555 TABLE Clinical Asthma Evaluation Score 50.1 70–100 in 21% O2 None ,70 in 21% O2 ,70 in 40% O2 In 21% O2 In 40% O2 Inspiratory breath sounds Normal Unequal Decreased to absent Accessory muscles used None Moderate Maximal Expiratory wheezing None Moderate Marked Cerebral function Normal Depressed or agitated Coma Pao2 (torr) or Cyanosis Pao2, Partial pressure of oxygen Data from Wood DW, Downes JJ, Lecks HI A clinical scoring system for the diagnosis of respiratory failure Preliminary report on childhood status asthmaticus Am J Dis Child 1972;123:227–228 History The child with an asthma exacerbation usually presents with complaints of difficulty breathing and shortness of breath The presence of these complaints in a child known to have had previous asthma exacerbations is highly suggestive of the diagnosis A significant percentage of children have a history of a coexisting viral upper respiratory infection, whereas some describe exposure to known allergic triggers Circumstances permitting, one should inquire about the presence of high-risk factors (see earlier section) for severe disease and the adequacy of maintenance therapy Physical Examination Children with severe forms of acute asthma commonly present with tachypnea, diaphoresis, increased use of accessory muscles, and nasal flaring Sick nonverbal children may appear anxious, agitated, or simply unable to be distracted from the task of breathing Speech in older children occurs in short phrases because of the rapid respiratory rate The presence of intercostal, subcostal, and suprasternal retractions; nasal flaring; inability to speak in full sentences; and agitation are signs of impending respiratory failure Evolution or persistence of these signs is followed by slower labored breathing, confusion or obtundation, and respiratory arrest Wheezing, which is a common clinical finding in patients with acute asthma exacerbations, is the audible manifestation of turbulent airflow in the intrathoracic intrapulmonary airways Wheezing is usually expiratory as a result of the dynamic compression of conducting airways, but it can be inspiratory as well Wheezing in persons with severe asthma usually is bilateral Asymmetric wheezing suggests regional mucous plugging, atelectasis, pneumothorax, or the presence of a foreign body The degree of wheezing correlates poorly with disease severity62 because wheezes are heard only in the presence of sufficient airflow A patient with severe airway obstruction and very limited airflow may have a silent chest upon initial examination, but loud wheezes may develop after effective therapy Likewise, in a patient with loud wheezes who continues to worsen, a reduction in wheezing may occur as a prelude to respiratory failure An objective assessment of disease severity is important in evaluating a patient’s response to therapy Several asthma severity scores are widely used in clinical practice, including the Clinical Asthma Score, Pediatric Asthma Severity Score, Acute Asthma Intensity Research Score, and the Preschool Respiratory Assessment Measure.63–65 Wood and colleagues66 developed a practical clinical asthma score specifically intended to identify near-fatal asthma It is composed of five variables with three different grades that allow for semiquantitative assessment of disease severity (Table 50.1) and correlates well with the need for prolonged bronchodilator therapy and hospitalization.67 Increasing scores correlate with progressive hypercarbia, and scores greater than often indicate respiratory failure However, although clinical asthma scores seem to be useful for assessing the severity of an attack, they are not as effective in prospectively identifying patients who require prolonged hospitalization or in whom complications and subsequent disability develop.68,69 There is still a need for a single scoring system with sufficient validity, reliability, and utility for universal clinical application.70 A less frequently used but more objective method of assessing disease severity and progression in patients with severe asthma is measurement of the pulsus paradoxus Originally described by Adolf Kussmaul71 in a patient with constrictive pericarditis, pulsus paradoxus also is observed in conditions in which pleural pressure swings are exaggerated, such as critical asthma The simplest definition of pulsus paradoxus is an exaggeration of the physiologic inspiratory decrease in systolic blood pressure72 (Fig 50.2) Several mechanisms have been proposed for the occurrence of pulsus paradoxus in persons with asthma It is likely that various mechanisms contribute differently depending on the adequacy of intravascular volume, magnitude of pleural pressure swings, degree of pulmonary hyperinflation, and state of cardiac contractility These mechanisms include cyclic increases in left ventricular afterload and in venous return to the right heart59 from highly negative intrapleural pressure during inspiration73; decreased left ventricular preload as a result of inspiratory blood 556 S E C T I O N V Pediatric Critical Care: Pulmonary ∆ = 25 mm Hg Exp Insp Exp edema, cardiomegaly, or clinically important atelectasis In children presenting with a first episode of severe wheezing, a chest radiograph may help diagnose anatomic abnormalities (such as vascular rings or a right-sided aortic arch) or foreign bodies We generally obtain a chest radiograph in patients who are sick enough to require monitoring and treatment in the ICU to exclude the possibility of additional extrapulmonary or airspace diseases In our practice, this has revealed conditions such as mediastinal tumors, congestive heart failure, and anomalous left coronary artery in children diagnosed with asthma in the pre-ICU setting Laboratory Data Arterial Blood Gas Analysis • Fig 50.2 Pressure recording from a radial artery catheter of a spontane- ously breathing patient with airway obstruction Top, Abnormally high pulsus paradoxus of 25 mm Hg is measured as the difference (D) in systolic blood pressure between expiration (Exp) and inspiration (Insp) Bottom, Normal slight physiologic variation of the systolic blood pressure as a function of the respiratory cycle 12 hours after onset of treatment pooling in the pulmonary vasculature74; impaired left ventricular diastolic filling caused by a leftward shift of the interventricular septum resulting from increased venous return to the right heart75; constraint of cardiac filling because of longitudinal inspiratory deformation of the pericardium59; and increased right ventricular afterload with decreased filling of the left ventricle as a result of hyperinflation, acidosis, and hypoxia.76 The pulsus paradoxus can be measured easily in a patient who is spontaneously breathing by transducing pressure signals from an indwelling arterial catheter Alternatively, it can be measured with a manual sphygmomanometer by inflating the cuff 20 mm Hg above the systolic pressure and then deflating it slowly until the first Korotkoff sounds are heard (systolic blood pressure) Initially, Korotkoff sounds are heard only during expiration The cuff is then carefully deflated until the point at which the sounds are appreciated during both inspiration and expiration and correspond to every heartbeat The difference between the highest systolic pressure and the pressure at which all Korotkoff sounds are heard is the magnitude of the pulsus paradoxus During normal breathing, this difference is less than mm Hg, but it is generally greater than 10 mm Hg during acute asthma exacerbations and greater than 20 mm Hg in patients with more severe disease.77 Changes in the magnitude of pulsus paradoxus during the course of therapy are good indicators of disease severity and clinical response to treatment.59,77 Radiography A chest radiograph is not routinely indicated in acute severe asthma20 but may be useful in patients suspected of having a pneumothorax, pneumomediastinum, pneumonia, pulmonary Arterial blood gas measurements provide objective information on the adequacy of ventilation and oxygenation of the patient with asthma The typical blood gas abnormality in the early phase of acute asthma is hypoxemia with hypocapnia (partial pressure of carbon dioxide [Paco2] ,35 torr), reflecting hyperventilation.78 With worsening airway obstruction, Paco2 measurements return to the normal range of approximately 40 torr However, this “normal” Paco2 should not be viewed as reassuring when taken in the context of prolonged expiratory time, tachypnea, and accessory muscle use.79 In fact, Paco2 greater than 40 torr in a patient with a severe asthma exacerbation should be interpreted as a sign of evolving respiratory muscle fatigue and warrants close clinical observation Sicker patients often exhibit a mixed respiratory and metabolic acidosis.80 Lactic acidosis is frequently encountered in these patients and usually is secondary to excess sympathetic stimulation (type B lactic acidosis),81 though it may also reflect tissue hypoxia and impending respiratory failure.82 Measurement of the lactate/pyruvate ratio may help distinguish the etiology of lactic acidosis Abnormal arterial blood gas measurements alone should not be the basis for the decision of whether to intubate a child with asthma Intubation should be dictated by the overall clinical status and may come before blood gas aberrations reach the criteria for respiratory failure used in other diseases In children requiring mechanical ventilation, frequent blood gas measurements are essential to monitor disease progression and the adequacy of ventilatory support Additionally, blood gas analysis may be the only means to diagnose significant hypercarbia in critical asthma patients who have neurologic comorbidities or static encephalopathy and those receiving sedative medications Electrolytes and Complete Blood Cell Count Routine blood chemistry analysis and blood cell counts generally are not helpful in patients with acute severe asthma Children who present with a protracted asthma attack may have evidence of dehydration with elevated blood urea nitrogen or decreased bicarbonate because of inadequate oral fluid intake and increased insensible water losses Patients undergoing repeated treatments with nebulized or intravenous (IV) b-agonist agents might show evidence of hypokalemia from the potassium shift to the intracellular space The white blood cell count usually is normal, although some atopic patients may exhibit elevated eosinophil counts The presence of leukocytosis does not necessarily indicate infection and often is related to adaptive stress or the administration of exogenous corticosteroids As with chest radiography, many intensivists routinely obtain CHAPTER 50 Asthma laboratory analysis at PICU admission to evaluate for additional diagnoses beyond asthma Muscle Enzymes Myoglobin, a heme protein present in skeletal and cardiac muscle, is often elevated in patients with near-fatal asthma.83 At least onethird of patients with acute severe asthma exhibit an elevated plasma creatine kinase (CK).83 Although such elevations seem to be more pronounced in patients with marked acidemia or with more severe respiratory insufficiency, a convincing correlation between disease severity and CK elevation has not been established.83 Though the CK-myocardial bound isoenzyme is increased in some patients, most elevations in CK are not secondary to cardiac disease.83 However, patients with acute severe asthma have risk factors for acute cardiac injury, including hypoxemia, acidosis, and high myocardial energy demand Troponin may be elevated even in patients without known cardiac disease In one study, 36% of critical asthma patients without known cardiac disease (n 64) who had troponin measured as part of clinical care had elevated levels,84 and all eight cases of troponin greater than 0.5 ng/mL (range, 1.0–12.6 ng/mL) were associated with sustained diastolic hypotension Diastolic hypotension develops in many children treated with continuous b-agonist medications, potentially decreasing coronary perfusion,84 which should be monitored Electrocardiography Patients with significant airway obstruction and hyperinflation may exhibit a change in the mean frontal P-wave vector A P-wave axis greater than 60 degrees has been associated with hyperinflation in both pediatric and adult patients with airway obstruction and is thought to represent positional atrial changes caused by inferior displacement of the diaphragm.85 Twelve-lead electrocardiography (ECG) and continuous cardiac monitoring are valuable tools in the care of patients with critical asthma These patients usually receive high doses of b-agonist drugs and may show evidence of hypokalemia (low-voltage T waves) or cardiac arrhythmias.86,87 The already increased myocardial energy demand resulting from airway obstruction is compounded by the chronotropic and vasodilatory effects of b-agonist drugs and may lead to myocardial ischemia, particularly in adult patients with restricted coronary perfusion Pediatric patients may exhibit ECG and enzymatic evidence of myocardial ischemia, particularly during treatment with intravenously administered isoproterenol.88 However, despite the fact that a study reported a high percentage (66%) of patients exhibiting nonspecific ST-segment changes or other criteria suggestive of ischemia, these changes were not well correlated with initiation of terbutaline therapy or elevations in cardiac troponin T.89 Spirometry Measurement of peak expiratory flow rates can be used to estimate the degree of airway obstruction and response to therapy in patients presenting to the emergency department with an acute asthma attack This is less useful in the ICU because sick children with severe respiratory distress may be unable to perform an adequate forced expiratory maneuver Measurements also may not be reliable in younger patients who are incapable of coordinating a rapid forced expiratory effort 557 Treatment Initial Management in the Emergency Department Pediatric patients with mild acute asthma exacerbations generally are treated in the emergency department with one or more doses of an inhaled b-agonist, such as albuterol (salbutamol) Most of these patients also should receive a systemic corticosteroid, such as prednisone, and then can be sent home to complete a 3- to 5-day course of therapy Patients with mild disease often respond well to initial treatment and not require the attention of a pediatric intensivist Patients with moderate or severe acute asthma exacerbations require aggressive treatment from the outset Because most patients with moderate or severe exacerbations have enough intrapulmonary shunt to result in hypoxemia, supplemental oxygen therapy should be initiated at the earliest time possible The inspired oxygen can be adjusted once peripheral capillary oxygen saturation (Spo2) is measured with a goal above 92% It should not be assumed that ventilation is adequate in a patient with normal Spo2 during the administration of supplemental oxygen therapy Nebulized b-agonist agents such as albuterol are the most commonly used first-line therapy in the emergency department The usual albuterol dose ranges between 0.05 and 0.15 mg/kg, diluted with or mL of normal saline solution However, from a practical standpoint, patients weighing 20 kg or more typically are administered 5-mg doses, whereas patients weighing less than 20 kg receive 2.5-mg doses Albuterol doses are repeated every 20 minutes during the first hour, with the need for additional doses dictated by clinical response Patients with moderate or severe acute asthma should also receive a dose of systemic corticosteroid in the emergency department, typically prior to the second dose of albuterol Prednisone (2 mg/kg) can be administered orally and generally is well tolerated Oral prednisone is superior to inhaled fluticasone in children with severe asthma, as evidenced by greater improvement in pulmonary function and lower hospitalization rates.90 Alternatively, dexamethasone administered as a single intramuscular dose (0.3–1.7 mg/kg) or enterally (0.6 mg/kg daily for days) has been shown to be equivalent to 5-day courses of prednisone with less emesis.91 The role of corticosteroids in reversing an acute asthma exacerbation in the emergency department has been the subject of debate, considering that these drugs require at least to hours for peak effects to be manifested.92 However, regardless of considerations about onset of action, acute suppression of inflammation is a cornerstone of acute asthma treatment, and there is evidence that early administration may reduce the rate of hospitalization.93 In addition, corticosteroids increase the density, affinity, and functionality of b-adrenergic receptors in both normal and catecholamine-desensitized conditions, thus increasing the efficacy of coadministered b-adrenergic agents.94 This mechanism may explain, at least in part, the rapid clinical improvement exhibited by some patients treated with a combination of corticosteroid and b-adrenergic agents.95 Patients with more severe asthma exacerbations, those unable to tolerate oral medication because of respiratory distress or emesis, or those with a history of nausea during intensive b-agonist therapy should be given parenteral corticosteroids such as methylprednisolone (2 mg/kg administered intravenously, followed by 0.5–1 mg/kg per dose administered intravenously every hours) ... approximately cm H2O during normal breathing.56 The increased CHAPTER 50 Asthma muscle work is accompanied by an increase in blood flow to the diaphragm, but this flow often is insufficient to meet... which all Korotkoff sounds are heard is the magnitude of the pulsus paradoxus During normal breathing, this difference is less than mm Hg, but it is generally greater than 10 mm Hg during acute asthma... the circulatory system The highly negative intrapleural pressures generated by spontaneously breathing patients during inspiration favor transcapillary fluid movement into the interstitium and