558 SECTION V Pediatric Critical Care Pulmonary Inhaled or nebulized anticholinergic agents such as ipratro pium bromide are a common adjunct to the treatment of asthma exacerbations in the emergency[.]
558 S E C T I O N V Pediatric Critical Care: Pulmonary Inhaled or nebulized anticholinergic agents such as ipratropium bromide are a common adjunct to the treatment of asthma exacerbations in the emergency department In patients treated with one dose of a corticosteroid, use of ipratropium bromide (500 mg/2.5 mL) in conjunction with the second and third albuterol doses has been associated with greater clinical improvement96 and reduced hospitalization rates compared with corticosteroid and albuterol alone.97 Magnesium sulfate administered as a single intravenous bolus (25–40 mg/kg over 20 minutes) has been shown to reduce hospitalization rates in children with moderate to severe asthma when administered in the emergency department.98,99 In practice, magnesium sulfate is more commonly used as an adjunct in severe asthma to prevent respiratory failure and ICU admission.100 Admission Criteria Most patients with an acute asthma exacerbation respond to treatment in the emergency department and are discharged home Among patients whose symptoms persist despite initial treatment, most can be managed safely in the general pediatric inpatient ward Indications for hospitalization after treatment in the emergency department are loosely defined but may include (1) an inadequate response to three or four aerosol treatments; (2) relapse of respiratory distress within hour of receiving treatment with aerosols and steroids; (3) persistent Spo2 measurements of less than 91% in room air; (4) the need for oxygen therapy; (5) a significant reduction in peak expiratory flow rate, especially with a poor response to bronchodilators; (6) having unreliable family support or being unable to comply with outpatient treatment; and (7) multiple visits for the same episode.101,102 Patients who require higher levels of monitoring, more invasive and aggressive treatment, or who deteriorate during hospitalization in the general pediatric ward should be admitted to the PICU Management in the Intensive Care Unit General Patients with critical asthma who are admitted to the ICU represent a heterogeneous group, thus requiring different levels of monitoring and treatment However, all patients who are sick enough to warrant admission to the ICU should be monitored using continuous ECG tracing, continuous respiratory rate, noninvasive blood pressures, and Spo2 Sicker patients who require frequent blood sampling will benefit from an indwelling arterial catheter Patients in respiratory failure requiring mechanical ventilation should have reliable and adequate central venous access Oxygen Patients with more severe asthma exacerbations universally exhibit hypoxemia as a result of intrapulmonary shunts caused by mucus plugging, atelectasis, and hyperinflation Treatment with bagonist agents also contributes to hypoxemia by abolishing regional pulmonary hypoxic vasoconstriction and increasing intrapulmonary shunt.103,104 Patients may have hypoxemia despite a normal-appearing chest radiograph, as regional hyperinflation may result in the conversion of lung segments from West zones and to zone 1, increasing ventilation-perfusion mismatch Therefore, humidified oxygen should be used for bronchodilator nebulization and continuously between treatments.105 Supplemental oxygen can safely be incorporated into the treatment algorithm, because, unlike in some adult patients with severe chronic obstructive pulmonary disease106 or asthma,107 no evidence exists to suggest that supplemental oxygen suppresses the respiratory drive in children with critical asthma Fluids Patients with critical asthma usually present with decreased total body water because of decreased oral fluid intake and increased insensible water losses Therefore, most patients require some degree of volume expansion This should be carefully balanced with the need to avoid overhydration because of the propensity for transcapillary fluid migration and alveolar flooding exhibited by some patients with large swings in intrathoracic pressures, potentially resulting in worse clinical outcomes.108 The need for rapid fluid expansion often becomes obvious shortly after intubation of patients with low intravascular volumes who are receiving b-agonist agents Patients should remain NPO and on isotonic intravenous fluids until an improvement in respiratory status allows for the safe initiation of enteral nutrition Corticosteroids Corticosteroids play a central role in the treatment of patients with critical and near-fatal asthma, considering that these conditions are predominantly inflammatory in nature Glucocorticosteroid agents modulate airway inflammation by a number of mechanisms, including direct interaction with cytosolic receptors and glucocorticosteroid response elements in gene promoters and indirect effects on the binding of transcription factors (such as nuclear factor–kB) and on other cell-signaling processes, such as posttranscriptional events.109 Gene products suppressed by glucocorticosteroid agents include a wide range of cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-11, IL-12, IL-13, tumor necrosis factor-a, and granulocyte-macrophage colony-stimulating factor), adhesion molecules (intracellular adhesion molecule-1 and vascular cell adhesion molecule-1), and inducible enzymes, including NO synthase and cyclooxygenase-2.110 Transcription of other genes, such as lipocortin-1 and the b2-adrenergic receptor, may be enhanced.110 Glucocorticosteroid agents also decrease airway mucus production, reduce inflammatory cell infiltration and activation, and attenuate capillary permeability.111–113 In children with critical or near-fatal asthma, glucocorticosteroids should be administered by the IV route The oral route may be used in selected cases, but inhaled glucocorticosteroids play no role in the treatment of the hospitalized patient.37,90 The most common agent used in the United States is methylprednisolone due to its wide availability as an IV preparation and lack of mineralocorticoid effects The usual dose of methylprednisolone is 0.5 to mg/kg per dose, administered IV every hours Hydrocortisone, an agent with both glucocorticoid and mineralocorticoid activity, can be used as an alternative at doses of to mg/kg per dose, administered IV every hours Short courses of steroids typically are well tolerated without significant adverse effects.113 However, hypertension, hyperglycemia, mood disorders, and serious viral infections, such as fatal varicella, have been reported in previously well patients with asthma who have received glucocorticosteroid drugs.113–115 Duration of corticosteroid therapy is dictated by the severity of illness and clinical response, but it should be noted that airway inflammation continues long after the clinical symptoms improve Once initiated, treatment CHAPTER 50 Asthma with systemic corticosteroids is continued for to days and followed by long-term inhaled steroids Longer treatment courses necessitate gradual weaning of the drug to decrease the chances of symptomatic adrenal insufficiency or relapse Prophylaxis with an H2 blocker or proton pump inhibitor should be considered because of the possibility of steroid-associated gastritis and gastric perforation.116 b-Agonists The b-agonist properties of the sympathomimetic agents cause bronchial smooth muscle relaxation and, hence, bronchodilation These agents also can increase diaphragmatic contractility, enhance mucociliary clearance, and inhibit bronchospastic mediators from mast cells.117 Therefore b-agonists, along with systemic corticosteroids, are the mainstay of pharmacotherapy in persons with critical and near-fatal asthma b2-receptor selectivity is desirable to avoid adverse effects of nonselective a- and b1-adrenergic receptor stimulation However, despite relative b2 selectivity, cardiovascular adverse effects remain a dose-limiting factor The relative potency of various agents for the b2 receptor is as follows: isoproterenol fenoterol albuterol terbutaline isoetharine metaproterenol.118 Of these, only albuterol and terbutaline are widely used in clinical practice Once bound to the b-adrenergic receptor, b-agonists activate adenyl cyclase, resulting in increased intracellular cyclic adenosine monophosphate (cAMP) levels, which leads to bronchial and vascular smooth muscle relaxation Dose-response curves demonstrate that large dose increases fail to enhance bronchodilation significantly However, as the degree of bronchial constriction increases, the bronchodilation dose-response curve shifts to the right, indicating the need for a higher dose to achieve the desired response.118 In persons with near-fatal asthma, parenteral and aerosol routes of administration are used exclusively Traditional therapy for persons with critical asthma previously included subcutaneous doses of epinephrine, but epinephrine is no longer widely used because of the development of newer, more selective bagonist agents with longer durations of action and fewer adverse effects The most frequent adverse effects of b-agonist agents are skeletal muscle tremor, nausea, and tachycardia These adverse effects are common to nonselective and selective b2-agonist drugs administered either by IV or inhalational routes Other cardiovascular adverse effects include blood pressure instability (predominantly diastolic hypotension) and cardiac dysrhythmias.119,120 Myocardial ischemia has been well documented as a serious complication of IV (and inhalational) isoproterenol administration to children with critical asthma.88,121 However, continuous IV infusions of terbutaline generally are safe and are not associated with significant cardiotoxicity.89 Prolongation of the QTc interval and hypokalemia have been observed during IV infusions of b-agonist drugs.122 Hypokalemia occurs even with a relatively stable total body potassium and is the result of intracellular potassium shifting resultant, at least in part, from an increased number of sodium-potassium pumps and not from augmented potassium elimination.123 Therefore, supraphysiologic potassium supplementation is rarely necessary A common significant adverse effect of b-agonist agents is hypoxemia This is related to drug-mediated pulmonary vasodilation overcoming local hypoxic vasoconstriction increasing perfusion to poorly ventilated lung units and intrapulmonary shunt.103,104 559 Albuterol Albuterol is the most b2-specific aerosol agent available in the United States It usually is administered every 20 minutes during the initial phase of treatment at a dose of 0.05 to 0.15 mg/kg The optimal dose and frequency of albuterol are variable and affected by spontaneous tidal volume, breathing pattern, device, and technique On average, less than 1% of the nebulized drug is deposited in the lung.124 After the initial series of three albuterol treatments, continuous albuterol nebulization should be started for patients who require nebulization treatments more frequently than every hour Continuous albuterol nebulization appears to be superior to repeated intermittent dosing and does not cause significant cardiotoxicity.125–127 A small prospective, randomized study in children with critical asthma and impending respiratory failure indicated that children treated with continuous albuterol nebulization had more rapid clinical improvement and shorter hospitalizations than children treated with intermittent albuterol doses.126 Continuous administration of albuterol also was associated with more efficient allocation of respiratory therapists’ time and could offer the added advantage of more hours of uninterrupted sleep to patients.128 The usual dose of continuously administered albuterol ranges between 0.15 and 0.45 mg/ kg/h, with a maximum dose of 20 mg/h Higher doses of albuterol have been used in patients who are unresponsive to standard treatment.129 However, we not support this practice, because the intensification of adverse effects usually outweighs any small incremental gain in bronchodilatory effect It should be remembered that a major component of bronchial obstruction in severe asthma is from airway wall edema and mucus obstruction of the airways, neither of which is responsive to bronchodilators Albuterol is a 50:50 mixture of R-albuterol (levalbuterol), the active enantiomer that causes bronchodilation, and S-albuterol, which was thought to be inactive in humans Levalbuterol, the pure R-isomer, is approved for use in the United States as a preservative-free nebulizer solution The purported advantage of levalbuterol over albuterol stems from the fact that S-albuterol may not be completely inert and has a longer elimination halflife than R-albuterol.130,131 However, the notion that S-albuterol is not inert and that it is capable of clinically significant adverse effects is not universally accepted.132–134 A large randomized controlled trial of levalbuterol versus racemic albuterol in children with asthma demonstrated a decreased rate of hospitalization in patients treated with levalbuterol.135 However, this study had methodological problems, as the primary outcome variable (rate of hospital admission) was left to the discretion of the treating physicians, and none of the secondary outcome variables were significantly different between treatment groups once the patients had been admitted to the hospital.135 More recent randomized clinical studies in children with asthma failed to show that levalbuterol is superior to racemic albuterol.136–138 The notion that levalbuterol causes less tachycardia than racemic albuterol has also been disproven.139 Furthermore, although the cost of levalbuterol has decreased significantly in the past few years, this drug continues to be more expensive than albuterol (M.L Biros, PharmD, Rainbow Babies & Children’s Hospital, personal communication, 2019) Considering the lower cost of albuterol and the lack of clinical evidence supporting the superiority of levalbuterol, we favor albuterol as the routine bronchodilator of choice in children with critical and near-fatal asthma 560 S E C T I O N V Pediatric Critical Care: Pulmonary Intravenously administered albuterol is not available in the United States However, the efficacy of albuterol infusions in patients with severe asthma has been well established in countries where the IV preparation is available.140,141 Terbutaline Terbutaline is a relatively selective b2-agonist with a mechanism of action similar to albuterol It is the most commonly used parenteral b-agonist in the United States and is available for nebulization, subcutaneous injection, and IV administration Because of its lower b1-receptor affinity, subcutaneous administration of terbutaline has largely supplanted the use of epinephrine in patients with severe acute asthma Subcutaneous terbutaline is very rarely used in the PICU; it is reserved for patients with acute worsening of respiratory status who not have vascular access and in whom access cannot be easily obtained Subcutaneous terbutaline is more commonly used in the management of sick patients in the emergency department and before hospital contact The usual subcutaneous terbutaline dose is 0.01 mg/kg per dose (maximum 0.25 mg) subcutaneously every 20 minutes for three doses, as necessary Terbutaline is commonly and safely used in the PICU by IV infusion.142 This therapy is indicated for patients with critical asthma who fail to improve or who show signs of deterioration during treatment with nebulized b2-agonists, ipratropium bromide, and steroids The usual range of IV terbutaline dosage is 0.1 to 10 mg/kg per minute, as a continuous infusion prepared in 0.9% normal saline solution or D5W.119 In our clinical experience, however, most patients are started on a dose of mg/kg per minute, and the dose is titrated to effect, with doses higher than mg/kg per minute rarely necessary Patients starting therapy at doses lower than mg/kg per minute can be given a loading dose of 10 mg/kg over 10 minutes to accelerate the onset of action Anticholinergic Agents Anticholinergic agents have become an important part of the treatment of children with severe acute asthma The typical anticholinergic agent used in treating patients with asthma is ipratropium bromide, a quaternary ammonium compound formed by the introduction of an isopropyl group to the N atom of atropine Unlike atropine (a tertiary ammonium compound), ipratropium bromide does not cross the blood-brain barrier and does not cause central anticholinergic adverse effects Considering that parasympathetic input influences bronchial smooth muscle tone, ipratropium bromide can produce bronchodilation by inhibition of cholinergic-mediated bronchospasm.143 An important property of ipratropium bromide is the lack of negative effect on ciliary bronchial epithelium, unlike the marked inhibition of ciliary beating and mucociliary clearance produced by atropine.143 Nebulized ipratropium bromide (250- to 500-mg doses) can be used every 20 minutes during the first hour in the emergency department The recommended dose for continuation therapy is 250 to 500 mg every hours After inhalation, peak responses usually develop over 30 to 90 minutes, and clinical effects may persist for more than hours.143 Systemic effects are minimal because less than 1% of an inhaled dose of ipratropium bromide is absorbed into the circulation However, extrapulmonary effects, such as mydriasis and blurred vision, have been reported from inadvertent topical ocular absorption of the drug.144,145 The addition of ipratropium bromide to nebulized albuterol in the treatment of bronchospasm makes pharmacologic sense because albuterol causes bronchodilation by increasing cAMP levels, while the effect of ipratropium bromide is mediated by a decrease in cyclic guanosine monophosphate The combined use of ipratropium bromide and nebulized albuterol to treat children with asthma who present to the emergency department has proved to be cost effective Magnesium Sulfate Magnesium is a physiologic calcium antagonist that inhibits calcium uptake and relaxes bronchial smooth muscle It has been known for more than 60 years that magnesium causes bronchorelaxation in patients with asthma,148 but its use as an adjunct in treating patients with severe asthma has occurred only recently Numerous reports, case series, and randomized controlled trials have suggested clinical improvement when asthmatic patients receive IV magnesium sulfate infusions in the emergency department or ICU.149,150 While there is some evidence that magnesium is as effective as albuterol when delivered by nebulization151 and has been used successfully as a liquid vehicle for albuterol nebulization,152 a larger trial failed to show a significant benefit on hospital length of stay.153 The indication for IV magnesium sulfate in children with critical or near-fatal asthma is still unclear because of the paucity of randomized controlled trials Some studies suggest that magnesium sulfate infusions are associated with significant improvements in short-term pulmonary function.154–156 Another study failed to show improvement in disease severity or a reduction in hospitalization rates.99 More recent studies indicate an association between magnesium sulfate use and longer durations of continuous albuterol and hospital length of stay but may be related to preferential use of magnesium in patients with more severe disease.157,158 The usual dose of magnesium sulfate in children with critical or near-fatal asthma is 25 to 40 mg/kg per dose, infused intravenously, over 20 to 30 minutes.154 The onset of clinical response is rapid (occurring in minutes) and generally is observed during the initial infusion Patients should be carefully monitored for adverse effects during the infusion, which include hypotension, nausea, and flushing Serious toxicity—such as cardiac arrhythmias, muscle weakness, areflexia, and respiratory depression—is not a significant concern with the use of magnesium sulfate in persons with acute asthma when used as directed The IV infusion of magnesium sulfate under controlled conditions is safe; a subset of patients with critical and near-fatal asthma clearly responds to this therapy, which may reduce the need for mechanical ventilator support.98,154–156,159 A systematic review of published randomized controlled trials supports the use of magnesium sulfate in addition to b2-agonist agents and systemic steroid drugs in the treatment of persons with acute severe asthma.160 Methylxanthine Agents Methylxanthine agents, as the name implies, are substances formed by the methylation of xanthine, and include caffeine, theobromine, and theophylline The water solubility of methyl xanthine agents is very low but can be greatly enhanced by the formation of complexes with a variety of compounds Most notably, the combination of theophylline and ethylenediamine yields aminophylline, a water-soluble salt The exact molecular mechanism of theophylline-mediated bronchodilation is unclear but is thought to involve its action as a phosphodiesterase-4 inhibitor, reducing the degradation of CHAPTER 50 Asthma cAMP This in turn mediates cellular responses that result in bronchial smooth muscle relaxation.161 Other mechanisms of action have been proposed, including inhibition of phosphoinositide 3-kinase activity,162 adenosine receptor antagonism,163 increasing histone deacetylase activity, stimulation of endogenous catecholamine release,164 prostaglandin antagonism,165 and alterations in intracellular calcium mobilization.166 Theophylline is also known to cause inhibition of afferent neuronal activity,167 leading to inhibition of bronchospasm mediated by reflex activation of cholinergic pathways Theophylline has antiinflammatory and immunomodulatory actions168 and is known to augment diaphragmatic contractility and increase respiratory drive.169 In isolated human bronchial preparations, in vitro theophylline concentrations greater than 70 mmol/L can induce a 50% reversal of bronchoconstriction.170 Such high local concentrations presumably would be achieved with plasma levels greater than 10 to 20 mg/mL.171 In clinical practice, however, this range poses a difficult problem because of the narrow window between therapeutic levels and toxicity, which often overlap The half-life of theophylline ranges from to hours.172 Therefore, aminophylline, which is equivalent to 80% theophylline, generally is administered as a continuous IV infusion to avoid significant fluctuations in serum concentrations Typically, a loading dose is given to achieve serum levels between 10 and 20 mg/mL Assuming a normal average volume of distribution, a mg/kg dose of theophylline (1.25 mg/kg of aminophylline) raises the serum concentration by mg/mL The loading dose should be administered over 20 minutes and should be followed immediately by the continuous infusion of the drug Empiric doses of aminophylline can be started for patients with normal hepatic and cardiac function as follows: infants younger than months, 0.5 mg/kg per hour; infants aged months to year, 0.85 to mg/kg per hour; children aged to years, mg/kg per hour; and children older than years, 0.75 mg/kg per hour Patients with compromised hepatic or cardiovascular function should be started at a dose of 0.25 mg/kg per hour Obese patients should have doses calculated on ideal body weight to prevent toxicity Serum drug levels should be monitored 30 to 60 minutes after the loading dose and frequently during the continuous infusion, considering that steady-state concentrations are not achieved until approximately five half-lives, which corresponds to 24 to 36 hours of infusion A number of studies in adults and children with acute asthma indicate that therapy with theophylline or aminophylline is of no clinical benefit.173–175 Randomized, placebo-controlled trials have tested the efficacy of aminophylline22 and theophylline176 in children with critical asthma Aminophylline treatment resulted in improved physiologic outcomes, such as oxygenation and pulmonary function testing, but did not decrease ICU length of stay and was associated with adverse effects, such as nausea and vomiting.22 Theophylline was associated with faster clinical improvement, but it had no effect on PICU length of stay and led to a significantly higher frequency of vomiting compared with control subjects.176 Use of these agents has decreased significantly considering the narrow therapeutic window (10–20 mg/mL) that often overlaps the toxicity (.15 mg/mL); the questionable evidence of clinical efficacy; and that methylxanthine agents have been associated with adverse effects ranging from nausea, vomiting, and fever to dyskinesias, seizures, and death In fact, methylxanthines were used in less than 6% of children with critical and near-fatal asthma admitted to PICUs in a multicenter study in the United States.20 With these considerations in mind, we consider using 561 methylxanthine agents only in occasional selected patients who fail to respond to maximal therapy with b-agonist agents, steroids, anticholinergic drugs, magnesium sulfate, and other adjuncts Helium-Oxygen Mixtures Helium is a biologically inert gas that is less dense than any gas except hydrogen and is about one-seventh as dense as air The medicinal application of helium and oxygen mixtures (heliox) in the treatment of asthma and extrathoracic airway obstruction has been known for over decades.177 Because of its low density, heliox reduces the Reynolds number This effect is associated with a reduced likelihood of turbulent gas flow while facilitating laminar gas flow in the airways, thus decreasing the work of breathing in situations associated with high airway resistance.178 Heliox provides a theoretical benefit in patients with obstructive lesions of the extrathoracic and intrathoracic airways Several reports advocate the benefit of heliox in the management of children with extrathoracic airway obstruction.178,179 The role of heliox in patients with asthma is less clear Research using heliox mixtures has demonstrated a greater percentage of lung particle retention and greater delivery of albuterol from both metered-dose inhalers and nebulizers,180,181 suggesting that one of the beneficial effects of heliox use in patients with asthma is improved deposition of aerosolized drugs While there is some evidence that 70%/30% heliox-driven continuous nebulized albuterol treatments are associated with a greater degree of clinical improvement compared with oxygen-driven continuous nebulized albuterol in children with moderate to severe asthma exacerbations,180 other studies have shown no significant improvement in hospital or ICU length of stay.182 The higher the needed fractional inspired oxygen concentration, the less effective the heliox mixture Heliox has been recommended by some investigators as a useful adjunct in adult patients with severe asthma, both during spontaneous breathing and mechanical ventilation.183–186 Anecdotal reports suggest that heliox is associated with improvement in pulmonary function in children with acute asthma.187,188 However, a small randomized crossover trial of heliox in spontaneously breathing patients with severe asthma failed to show improvement in pulmonary function or dyspnea scores.189 Additionally, a systematic review of seven prospective, controlled trials in children and adults did not support the use of heliox in patients with moderate or severe acute asthma.190 The paucity of well-executed randomized controlled studies makes it impossible to assess the therapeutic effect of heliox in children with asthma In addition, should heliox be beneficial in some patients, the duration of administration and optimal heliumoxygen mixture remain undetermined Until better evidence emerges, heliox remains an unproved therapy for pediatric asthma Its use should be restricted to individual attempts in selected patients with severe refractory critical or near-fatal asthma who not respond to conventional treatment.191 To get the full benefit from the lower gas density, 80:20 or 70:30 helium-oxygen mixtures must be used, limiting the therapy to those with low inspired oxygen needs Ketamine Ketamine hydrochloride is a dissociative anesthetic agent with bronchodilatory properties that is available in a solution for IV 562 S E C T I O N V Pediatric Critical Care: Pulmonary or intramuscular administration After IV administration, a sensation of dissociation is generally experienced within 15 seconds, followed by unconsciousness after another 30 seconds This reaction is followed by profound analgesia that lasts 40 to 60 minutes and amnesia that may persist for hours Some patients, particularly older children, may experience a postanesthesia emergence reaction with confusion, agitation, and hallucinations Usual ketamine doses not significantly affect hypoxic or hypercarbic respiratory drive Pharyngeal and laryngeal reflexes are maintained and, although the cough reflex is somewhat depressed, airway obstruction does not normally occur Aside from its anesthetic properties, ketamine causes sialorrhea and increases airway secretions, cardiac output, heart rate, blood pressure, metabolic rate, cerebral blood flow, and intracranial pressure.192 Pulmonary vascular resistance is not altered, and hypoxic pulmonary vasoconstriction is preserved Ketamine inhibits bronchospasm and lowers airway resistance, presumably through blockage of N-methyl-d-aspartate receptors in airway smooth muscle.193 The bronchodilatory effect of ketamine makes it an attractive agent in patients with asthma who require sedation and anesthesia for intubation or mechanical ventilation.194,195 However, the bronchodilatory effects of ketamine may be counteracted by the observed increase in airway secretions and sialorrhea Questions exist regarding the use of ketamine in nonintubated patients with critical asthma In the emergency department, ketamine infusion added to standard therapy of nonintubated patients has not shown a clinical benefit.196 However, limited evidence suggests that this therapy may be helpful in selected patients when trying to avoid the need for mechanical ventilation.197 In our experience, the administration of ketamine to nonintubated children with critical asthma frequently precedes the need to intubate and is rarely associated with significant and noticeable clinical improvement For this reason, attempts at administering ketamine to nonintubated children with severe critical asthma should always take place in the ICU under strictly monitored conditions and with personnel capable of rapidly establishing an airway for initiation of ventilatory support Ketamine usually is administered as an IV bolus of mg/kg, followed by a continuous infusion of to mg/kg per hour The resulting sialorrhea and increased airway secretions can be attenuated by administration of glycopyrrolate or atropine The concurrent use of benzodiazepines may attenuate the agitation and hallucinations in patients who experience emergence reactions following ketamine anesthesia Mechanical Ventilation Indications Only a small minority of patients with near-fatal asthma admitted to the PICU (10%–12%) require endotracheal intubation and mechanical ventilation.20 The indications for intubation are not precisely defined; the decision to proceed with intubation is based largely on clinical judgment Absolute indications are obvious and include cardiac or respiratory arrest, profound hypoxemia refractory to supplemental oxygen administration, and respiratory failure The decision to intubate should not be based solely on blood gas results However, the presence of a mixed respiratory and metabolic acidosis, persistent hypoxemia, and agitation or obtundation, despite maximal therapeutic efforts, indicate impending respiratory arrest and signal the urgent need to proceed with intubation and mechanical ventilation Noninvasive Ventilation Some patients with critical asthma will benefit from attempts to attenuate respiratory muscle fatigue through a trial of noninvasive ventilation.198,199 Noninvasive bilevel positive airway pressure should be employed so that the set inspiratory positive airway pressure (iPAP) assists the patient in overcoming the increased airway resistance and respiratory muscle fatigue, while the set expiratory positive airway pressure (ePAP) helps offset the intrinsic positive end-expiratory pressure (PEEP) and aids trigger synchrony We generally initiate noninvasive ventilation in spontaneous mode without a backup rate, with an iPAP of 10 cm H2O and an ePAP of cm H2O The iPAP can be titrated up based on the degree of inspiratory work of breathing and to generate a desired tidal volume of to mL/kg The ePAP may also be increased for improved synchrony and comfort, but levels greater than cm H2O are rarely indicated and may contribute to hyperinflation The use of bilevel positive airway pressure requires patient cooperation and a well-sealed mask, which may prove difficult in an anxious and agitated child with impending respiratory failure However, this should not preclude a trial of noninvasive ventilation, as many responders experience rapid improvement of respiratory distress and dyspnea, with attendant decrease in agitation.200,201 Intubation The intubation of patients with near-fatal asthma is complicated by the fact that these patients are, by definition, fatigued, acidotic, and often also hypoxemic or agitated Once the decision to intubate is reached, the procedure should be performed promptly by a skilled operator with experience in rapid sequence intubation Intubation should be preceded by the administration of an anesthetic, such as an opiate, propofol, or ketamine; a benzodiazepine; and a neuromuscular blocker Ketamine is the preferred anesthetic because of its properties as a bronchodilator Among the opiates, fentanyl is a widely available choice; morphine should be avoided because it is associated with histamine release and could, at least in theory, contribute to the allergic and inflammatory process A rapid-acting neuromuscular blocker such as succinylcholine can be used to induce chemical paralysis More commonly, a nondepolarizing neuromuscular blocker is used, such as vecuronium, rocuronium, or cisatracurium The patient should be preoxygenated with 100% oxygen by face mask during spontaneous breathing Assisted breathing with a bag-mask apparatus can be performed with care taken to avoid worsening of dynamic hyperinflation and gastric distension Whenever possible, a nasogastric tube should be placed in advance to decompress the stomach A cuffed endotracheal tube should be introduced and its placement confirmed by a colorimetric method or capnography, auscultation, and chest radiograph Special attention to the manual ventilation technique is needed to avoid fast rates that often are inadvertently applied immediately following intubation Rapid respiratory rates applied to intubated children with severe airway obstruction lead to iatrogenic hyperinflation, hypoxemia, and hemodynamic instability (hypotension) These patients require slow respiratory rates with very prolonged expiratory times to allow for adequate gas exchange and lung volumes A helpful technique is to use a stethoscope to auscultate for the disappearance of expiratory wheezes prior to starting the next inspiration The occurrence of oxygen desaturation and hypotension following ... persons with acute severe asthma.160 Methylxanthine Agents Methylxanthine agents, as the name implies, are substances formed by the methylation of xanthine, and include caffeine, theobromine, and... efficacy; and that methylxanthine agents have been associated with adverse effects ranging from nausea, vomiting, and fever to dyskinesias, seizures, and death In fact, methylxanthines were used in less... Reynolds number This effect is associated with a reduced likelihood of turbulent gas flow while facilitating laminar gas flow in the airways, thus decreasing the work of breathing in situations