SYMPOSIUM : PEDIATRIC I N T E N S I V E CARE

Indian J Pediatr 1990; 57 : 159-168 i

Guest Editor : N. danakiraman, U.S.A.

Lower Airway Obstruction in the PICU Susan A. Kecskes

Division of Critica/ Care, Department of Pediatrics, University of///inois at Chicago, Chicago,///inois, U.S.A.

Narrow airways, a more compliant chest wall, and relatively weaker muscles of respiration make infants and children more susceptible to lower respiratory problems. Bronchiolitis and asthma are the most commonly encountered causes of pediatric lower airway obstruction. The pathophysiology and clinical presentations of these conditions will be discussed before turning to management in the intensive care unit.

nally, there may be external compression of the airway by edema or masses? All four mechanisms may be active in patients with both bronchiolitis and asthma. Small changes in the radius of the airway greatly increase the resistance (R) to airflow. This relationship is expressed by Poiseuille's law.

R-

Pathophysiology

8 Ln jrra

(L = length of tube, n = viscosity of gas, r = radius of tube), As the patient attempts to inspire, he must generate more negative intrapleural pressures to overcome the increased resistance of narrowed airways. During expiration, airflow is impeded by the obstruction resulting in the decreased elastic recoil of the lung. The patient attempts to overcome this by lengthening the expiratory phase of respiration. In addition, the narrowed airways reach their critical closing pressure sooner resulting in air trapping. Clinically, the result of the lower airway obstruction is a prolonged expiratory phase of respiration, expiratory wheezing and

Obstruction of the lower airways may occur by four mechanisms. First, obstruction may occur by occlusion of the bronchlolar lumen with mucous, fluid or other debris. Second, the wails of the airway may cause narrowing of the lumen by contraction of the bronehiolar smooth muscle. Encroachment by the wall itself secondary to edema, inflammation, or mucous gland hypertrophy may cause obstruction. FiReprint requests : Dr. Susan A. Kecskes, Clinical Associate Professor of Pediatrics, University of Illinois at Chicago, College of Medicine, 840 South Wood Street, Chicago, Illinois 60612, U.S.A. 159

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hyperinflation of the lungs on physical examination and chest radiograph. The degree of obstruction can be measured by spirogram or peak flow meter in the cooperative child. Asthmatic patients have been extensively studied, although the age at which the required cooperation can be achieved limits the use of these measurements in bronchiolitis. Patients experiencing an exacerbation of their asthma have decreased peak expiratory flow (PEF), maximum expiratory flow rate (MEFR), and maximum mid-expiratory flow rate (MMEFR), as well as a low forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV1). Hypoxemia is characteristic of lower airway obstructive disease. Ventilation perfusion (V/O) mismatch is primarily responsible for the hypoxemia. '~ Airway obstruction in both bronchiolitis and asthma is unevenly distributed resulting in both hyperinflated and atelectatic alveoli. Pulmonary blood flow is simultaneously maldistributed leading to perfused, underventilated alveoli, as well as hyperventilated, underperfused alveoli. The resulting increase in physiologic dead space versus tidal volume should lead to decreased ventilation and rising PaCO 2. Initially, however, patients compensate by increasing their respiratory rate and tidal volume. Minute ventilation increases by 250% in the early phases of asthma. 4 The increase in minute ventilation is at the expense of work of breathing. Eventually, the child may tire and respiratory failure ensues. A normal or elevated pCO 2 in the prese.nce of ongoing evidence of lower airway obstruction indicates respiratory failure. Bronehiolitis

Bronchiolitis is characterized by acute

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inflammation of the lower airways as a result of viral infection in infants. The incidence is 11.4 cases per 100 children in the first year of life and it drops to 6 per 100 children during the second year of life: Overall mortality in infants hospitalized with respiratory syncytial virus .(RSV)induced bronchiolitis is 1 to 2%, but rises to 37% in patients with underlying congenital heart disease:

Etiology RSV is identified as the causative organism in 40 to 75% of hospitalized patients with bronchiolitis: Other organisms which have been associate with bronchiolitis are adenovirus types 3, 7 and 21, rhinovirus, parainfluenza virus, influenza virus, mumps virus and mycoplasma pneumoniae:

Pathology Bronchiolitis associated with RSV infection is characterized by inflammation and necrosis of the respiratory epithelium of the small airways. As the ciliated epithelium necrose, they are replaced by cuboidal cells, 8 without cilia. The patient is unable to mobilize the respiratory secretions and cellular debris clogging the lumens of the airways. Repair begins after 3 to 4 days in the basal layers with restoration of the cilia around 15 days. 9 In adenovirus associated bronchiolitis obli.terans, the damage to the respiratory epithelium is so severe that it is replaced by fibrotic tissue and the resultant scarring can obliterate the peripheral airways) ~

Clinical presentation Patients with bronchiolitis usually present after 2 to 3 days of upper respiratory tract symptoms, including rhinorrhea,

~ :

LOWI~AIRWAY~ I . L - ' I K ~

cough, and low-grade fever. Symptoms of lower respiratory disease include tachypnea, retractions, nasal flaring, and expiratory wheezing. Blood gases are characterized by hypoxemia in room air with oxygen saturations averaging 87%. Hypoxemia may persist for up to 7 weeks despite clinical improvement.H

Management General supportive measures are the mainstay of therapy for patients with bronchiolitis. Since hypoxemia is the hallmark of the disease, supplying the patient with humidified oxygen is essential. Oxygen may be administered by nasal cannula, mask, or hood to achieve oxygen saturation of 90% ,or greater. If oxygen saturation cannot be maintained by these methods or respiratory failure is imminent, the patient should be intubated and mechanically ventilated. Impending respiratory failure may be recognized by a rise in PaCO 2 above 40 torr in a patient with respiratory distress. Apnea and lethargy, indicating that the patient is tiring, are also indications for mechanical ventilation. Fluid management begins with the restoration of preexisting volume deficits. After the deficit is replaced, euvolemia should be maintained. To avoid pulmonary edema resulting from the negative intra-pleural pressures generated in airway obstruction, fluid overload should be avoided) 2 Cardiorespiratory monitoring is essential for patients in imPending respiratory failure. Oxygenatiori and ventilation should be monitored by intermittent arterial blood gases. Arterial catheters should be placed for frequent measurements. Non-invasive measurement of oxygen saturation with pulse oximetry allows continuous monitoring of oxygenation.

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Rapid identification of RSV is possible by enzyme-linked immunosorbent assay (ELISA) or flourescent antibody stain of nasal washings) 3 Viral cultures of respiratory secretions may be obtained, but results are rarely available in time for clinical application. Antiviral therapy is now available for bronchiolitis caused by RSV. Ribavirin is a synthetic nucleoside analog which inhibits viral protein synthesis by interfering with messenger RNA. 15 It is delivered in aerosolized form for 3 to 5 days. Particles small enough to reach the lower respiratory tract (1.2-1.3 pro) are generated by a small-particle aerosol generator (SPAG) unit (Viratek, ICN Pharmaceuticals)) s A 300 ml solution of ribavirin at a concentration of 20 mg/ml is delivered over 12 to 18 hours via the means being used to deliver oxygen to the patient e.g. oxyhood) 6 The manufacturer of ribavirin warns against its use with mechanical ventilation. The aerosolized drug may precipitate within the ventilator tubing, the exhalation valve, or the endotracheal tube leading to increased positive end expiratory pressures (PEEP) and subsequent barotrauma. 17 However, children who require mechanical ventilation are most likcly to benefit from ribavirin therapy) s Several investigators have reported successful use of ribavirin with mechanical ventilation: 7,~90utwater, et al, described a technique for delivering ribavirin via the SPAG unit with mechanical ventilation. The technique involves connecting the SPAG unit to the inspiratory limb of the ventilator. One-way valves are placed between the SPAG unit and the ventilator in the inspiratory limb to prevent precipitation of ribavirin in the ventilator and between the SPAG unit and its connection to the ventilator tubing 'to prevent

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volume being lost to the SPAG unit. Also, the exhalation valve is changed every four hours to prevent clogging. Patients should be carefully monitored during ribavirin administration for changes in peak inspiratory pressure or PEEP. 17 Deciding which patients will benefit from ribavirin is made difficult by both the high cost of the drug and the relatively low morbidity in most patients. Current recommendations by the Committee on Infectious Diseases of the American Academy of Pediatrics include infants known to be at high risk for severe infection such as those with congenital heart disease, bronchopulmonary dysplasia, other chronic lung disease, and immunosuppressed patients. In addition, patients with increased severity of disease as indicated by hypoxemia and respiratory failure as well as those patients less than six months of age or with underlying disease which may be complicated by RSV bronchiolitis should also receive ribavirin. TM Bronchodilators and steroids have not been proven to be helpful in the treatment of bronchiolitis?~ Asthma

Asthma is characterized by intermittent diffuse airway obstruction secondary to hyperreactivity of the airways and associated withcough, dyspnea and wheezing. Status asthmaticus is acute severe asthma which is unresponsive to outpatient therapy and may result in respiratory failure unless promptly reversed, z2

Etiology Bronchial smooth muscle spasm, airway edema and mucous plugging narrow the

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airways of asthmatic children. The hyperreactivity of the airways in asthma may be triggered several ways. Allergen exposure, along with increased IgE in these patients, stimulates mast cells to release substances such as histamine which cause airway smooth muscle to contract. Inflammation Of the bronchial mucosa and submucosa also occurs. Other triggers of hyper reactive airways are respiratory viral infections, exercise, emotional stress, gastroesophageal reflux and drugs such as fl-blockers and aspirin, z3

Clinicalpresentation Early clinical symptoms of status asthmaticus include cough, dyspnea and wheezing. The patient is usually tachypneic and tachycardic, although the latter may be secondary to stress or the use of adrenergic drugs. As the episode progresses, increased retractions and use of accessory muscles of respiration may be noted. Wheezing does not correlate well with increased severity of disease, but a decrease or absence of wheezing in the presence of increased dyspnea and respiratory effort may indicate respiratory failure?4 Pulsus paradoxus is an exaggeration of the normal 10 mm difference in systolic blood pressure between inspiration and expiration. An increase in pulsus paradoxus correlates well with increased airway obstruction in status asthmaticus. ~ Increasing lethargy or obtundation should be regarded as evidence of respiratory failure and the need for mechanical ventilation. The most critical laboratory test is the arterial blood gas. Early in the episode, . PaCO 2 is low secondary to the compensatory hyperventilation. As airway obstruc-

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tion worsens, the PaCO 2 may rise to norreal or above. A PaCO 2 of 40 to 45 torr in the presence of respiratory symptoms is evidence of impending respiratory failure?6 Hypoxemia is always present in status asthmaticus. However, it is usually mild to moderate and readily reversed with the administration of oxygen. Chest radiographs reveal hyperinflation, atelectasis, and peribronch!al thickening typical of lower airway obstruction (Fig. 1). Occasionally, an infdtrate will indicate an infectious origin of the asthmatic episode.

ging. Supportive measures are required to allow time for the therapy instituted to take effect. All patients with airway obstruction are hypoxemic and should receive supplemental humidified oxygen to maintain the PaO 2 at approximately 100 torr. Many patients are dehydrated when initially seen secondary to poor fluid intake and increased insensible respiratory loss. This may aggravate the mucous plugging contributing to airway obstruction. Dehydration should be corrected, but over hydration should be avoided. The very negative transpulmonary inspiratory pressures favour the development of pulmonary edema. 12 All patients should be on cardiorespiratory monitors. Hypoxemia and acidosis

Management Management of acute asthma is aimed at relieving the underlying broncho constriction, airway edema and mucous plug-

Fig. 1. Chest radiograph of asthmatic patient showinghyperinflation and flattened diaphragms.

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make these patients more susceptible 'to the cardiac effects of the drugs used to treat bronchospasm. Frequent arterial blood gases at 30 minute to four hour intervals are required to assess the development of respiratory failure. An indwelling arterial cannula facilitates these measurements. Continuous non-invasive monitoring of oxygen saturation is also used. Early in the course of an attack, the patient may respond to subcutaneous or aerosolized beta-agonists. The smooth muscle of the airways contain fl:adrenergic receptors which cause bronchodilation when stimulated. These receptors are also present in vascular smooth muscle and may lead to vasodilation and aggravate V/Q mismatch.27 Generally, the decreased airway obstruction outweighs this effect and results in clinical improvement. Epinephrine is both a.n a and fl-agonist. Given subcutaneously, it may reverse early bronchospam (Table 1). Use is limited by the development of tachyarrhythmias. Terbutaline is a selective fl2-agonist which may be Used subcutaneously, orally, Or by aerosol (Table. 1). 28 Used subcutaneously, it has a longer duration of action than epinephrine. 29 Aerosolized agonis~s have been shown to be effective bronchodilators With fewer cardiovascular effects.3~They may be administered by nebulization through the same means by which the patient is receiving oxygen. Choices include terbutaline, metaproterenol and albuterol (salbutamol). The drug is diluted to 3 ml and nebulized over 10 to 15 minutes (Table 1). Patients who do not adequately respond tO initial therapy are in status asthmaticus and require hospitalization. Theophylline has long been the mainstay of therapy for children in status asthmaticus. Known as a

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bronchodilator, its precise mechanism of action is not yet clear. Increased smooth muscle cyclic AMP levels are thought to result in bronchodilation.3~ There is also evidence that diaphragmatic contractility is improved by aminophylline (the intravenous form of theophylline).32In status asthmaticus, smoother control is obtained by using an intravenous loading dose of aminophylline followed by continuous intravenous infusion (Table 1). Effective therapeutic plasma level are 10 to 20 ~ g / m l : 3 Nausea, vomiting, irritability, arhythmias and seizures may occur at levels greater than 20 p g / m l : 4 Inhaled/~2-agonists may continue, to be used at intervals of one fo six hours (Table 1). They may be used alone or in addition to theophylline. Cortic.osteroids should be added to the therapeutic regimen of patients in status asthmaticus (Table 1). The precise mechanism of action is not known. Theories center on mechanisms which increase cyclic AMP promoting bronchodilation as well as anti-inflammat0rY effects.3s There is a six hour delay after intravenous administration before the first effects may be seen. 36 Short term use-is associated with minimal side effects. Patients who fail to respond to all of these measures are in impending respiratory failure and should be admitted to an ICU. In children, isoproterenol may be utilized as a continuous infusion in an attempt tO reverse bronchospasm (Table 1). Isoproterenol is a potent fl-agonist which causes both .bronchodilation and vasodilation. Careful monitoring of blood pressure, perfusion, and cardiac rate and rhythm is required during administration of this drug. Heart rates up to 200 beats/min may

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T~Lg 1. Drugs in Acute Asthma

Initial Therapy Epinephrine

1 : 1000 solution 0.01 ml/kg/dose subcutaneously repeated every 15 min • 3

TerbUtaline

0.01 mg/kg/dose subcutaneously repeated every 20 minx 2

Inhaled fl2-agonists : Terbutaline

1% solution 0.03 ml/kg (maximum 1 ml); dilute to 2.5 ml with normal saline; nebulize over 10-15 min

Metaproterenol

5% solution 0.01 ml/kg (maximum 0.4 ml); dilute to 2.5 ml with normal saline; nebulize over 10-15 min

Albuterol

0.5% solution 0.01 ml/kg (maximum 1 ml) dilute to 3.0 ml with normal saline nebulize over 10-15 min

Ttierapy for Status Asthmaticus Aminophylline (intravenous form of theophylline)

Theophylline = 0.8 x aminophylline loading dose* : 6 mg/kg intravenously over 20 min. Continuous infusion : young children (1-9 yr) : 0.8 mg/kg/hr older children (9-12 yr) : 0.7 mg/kg/hr adolescents : 0.5 mg/kg/hr Obtain theophylline levels at 1, 7 and 24 hours after start of continuous infusion and adjust dose to maintain serum theophylline level 10-20 ~g/ml

Inhaled B2-agonists As above Corticosteroids Methylprednisolone

Administer as above at 1-4 hour intervals 1 mg/kg intravenously repeat every 6 hours for 1-7 days

Severe Status Asthmaticus Isoproterenol

0.02% solution Start continuous intravenous infusion at 0.05 ttg/kg/min and increase by 0.05 ug/kg/min every 15 rain until bronchospasm improves, heart rate is greater than 200, or arrhythmias occur. Monitor blood pressure and heart rate continuously.

Continuously Inhaled B2-agonists

See Text

* If patient has already received a theophylline preparation, the loading dose needs to be adjusted. on the basis of a serum theophylline level.

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be tolerated' by children. Approximately 80-90% of patients with respiratory failure who receive isoproterenol may avoid intubation and mechanical ventilation.37~8 There has been recent interest in the use of continuous inhaled fl2-agonists in acute severe asthma. 39'4~Moler et al, studied the use of continuously nebulized terbutaline in status ~asthmaticus. Using 4 rag/ hr of terbutaline diluted to 10 ml with normal saline and nebulized for 3 to 37 hours, he demonstrated significant decreases in clinical asthma score and PaCO 2. No adverse side effects were noted. 4~ While further studies are needed, continuously nebulized fl2-agonists may be an effective alternative to continuous isoproterenol infusion and its complications. Some children progress to frank respiratory failure despite maximal pharmacologic therapy. Indications for intubation include cyanosis and agitation unrelieved by 40% oxygen, lethargy, arhythmias, and PaCO 2 greater than 50 torr and rising more than 5 torr per hour. Nasotracheal intubation is preferred because of stability. Patients with severe airway obstruction may require very high peak inspiratory pressure, up to 50 torr or more. To insure more adequate delivery of tidal volume, volume-cycled ventilators are preferred. Tidal volumes of 10 to 15 ml/kg and rates of 15 to 20 breaths/min with an inspiratory to expiratory ratio of 1 : 2 are recommended? 1 Sedation and neuromuscular blockade are necessary to ensure adequate ventilation at the lowest possible peak inspiratory pressures. Pancuronium bromide (0.1 mg/kg/hr), diazepam (0.3 mg/kg/every 4 hours), and/or morphine (0.1 mg/kg every 4 hours) are preferred? 1 Inspired oxygen is adjusted to maintain PaO 2 around 100 torr. Because of

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the already high airway pressures and risk of barotrauma, PEEP is not usually used. SUMMARY

Lower airway obstruction is one of the most frequent causes of admission to pediatric intensive care unit. A thorough understanding of the pathophysiology underlying the disease will lead to effective management and decreased mortality and morbidity. REFERENCES

1. West JB. Puhnonary Pathophysiology. Second Edition. Baltimore, Williams and Wilkins, 1982, pp 59-60. 2. Ledbetter MK, Bruck E, Farhi LE. Percussion of the under ventilated compartment of the lungs in asthmatic children. J Clin Invest 1964; 43 : 2233-2240. 3. Reynolds EOR. The effect of breathing 40 per cent oxygen on the arterial blood gas tensions of babies with bronchiolitis. J Pediatr 1963; 63 : 1135-1139. 4. Dowries JJ, Heiser MS. Status asthmaticus in children. In : Respiratory Failure in the Child. Gregory G (Ed). New York, Churchill Livingstone, 1981, p 107. 5. Henderson FW, Clyde WA, Collier AM et al. The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice. JPediatr 1979; 95 : 183-190. 6. MacDonald NE, Hall CB, Suffin SC et al. Respiratory syncytial virus infection in infants with congenital heart disease. N EnglJMed 1982; 307 : 397-400. 7. Carlsen KH, Orstavik I, Halvorsen K Viral infections of the respiratory tract in hospitalized children. Acta Paediatr Scand 1983; 72 : 53-58. 8. Wohl MEB, Chernick V. Bronchiolitis. Am Rev RespirDis 1978; 118 : 759-781. 9. Chantarojahasiri T, Nicholas DG, Rogers MC. Lower Airway Disease : Bronchioli-

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Intensive Care. Rogers MC (Ed). Baltimore, Williams and Wilkins, 1987, p 215. Aubler M, DeTroy A, Sampson T et al. Arninophylline improves diaphragmatic contractility. N Engl J Med 1981; 305 : 249-252. Nicholson DP, Chick TW. A.re:evaluation of parenteral aminophylline. Am Rev RespirDis 1973; 108 : 241-247. Weinberger ~d, Hendeles L. Commentary : Role of dialysis in the management of theophylline toxicity. Dev Pharmacol Ther 1980; 1:26-30. Dunlap NE, Fulmer JD. Corticosteroid therapy in asthma. Clin Chest Med 1984; 5 : 669-683. Pierson WE, Beirman CW, Kelley VC. A double-blind trial of corticosteroid therapy in status asthmasticus. Pediatrics 1974; 54 : 282-288. Wood DW, Downes JJ. Intravenous isoproterenol in the treatment of respiratory

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failure in childhood status asthrnaticus. AnnAllergy 1972; 31 : 607-610. Herman JJ, Noah ZL, Moody RR. Use of intravenous isoproterenol for status asthmaticus in children. Crit Care Med 1983; 11 : 716-720. Robertson CF, Smith F, Beck R et al. Response to frequent low doses of nebulized salbutamol in acute asthma J Pediatr. 1985; 106 : 672-674. Moler FW, Hurwitz ME, Custer JR. Improvement in clinical asthma score and PaCO 2 in children with severe asthma treated with continuously nebulized terbutaline. J Allergy .Clin bmnunol 1988; 81 : 1101-1109. Chantarojahasiri T, Nicholas DG, Rogers MC. Lower Airway Disease : Bronchiolitis and Asthma. In : Textbook of Pediatric Intensive Care. Rogers MC (Ed.) Baltimore, Williams and Wilkins, 1987, pp 223-224.

GOWER'S SIGN REVISITED Gower described the pattern of standing in 21 boys with pseudohypertrophic muscular dystrophy (DMD) in 1879. H e thought it to be pathognomonic for this disorder. Subsequently it has been shown to be present in other children with proximal musclc weakness. Dr.Gower emphasised two important features : (i) children adopting a prone position on all fours before attempting to stand, and (ii) children "walking up their legs". Although children with DMD first present to the doctors at median age of 2.7 years, the diagnosis is often delayed to 5.2 years. This delay is due to the failure to realise that the first feature of Gower sign (rolling prone before standing) appears early, while the second feature (walking up the 1.egs) is a late feature. However, the latter is more associated with Gower sign in the minds of pediatricians. It is suggested that if a child continues to roll prone when attempting to stand at 30 months he should be examined closely for the presence of proximal muscle weakness. Abstracted from: Wallace GB and Newborn R W . A r c h Dis Child 1989; 64 : 1317-1319