PERILS IN THE PEDIATRIC AIRWAY
From the University of Miami Miller School of Medicine’s Masters of Pediatrics: Contemporary and Future
Pediatrics
| WHEN THE BABY WHEEZES— Paul C. Stillwell, MD, Professor of Pediatrics, Phoenix Children’s Hospital, Phoenix,
AZ
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| Case example: male infant 3 mo of age; twin 36-wk pregnancy; cesarean delivery; grunting at 1 hr of age (had transient tachypnea
and small pneumothorax); required 8-day stay in neonatal intensive care unit (NICU); received nasal continuous
positive airway pressure (CPAP); not intubated and received antibiotics for possible pneumonia; no wheezing noted on discharge
summary; O2 saturation on room air normal; readmitted to hospital at 3 mo of age after 10 days of progressive cough,
congestion, and wheezing audible without stethoscope; other family members ill; findings on examination—O2 saturation
95%; wheezing in prolonged expiratory phase; umbilical hernia; chest x-ray normal; positive for respiratory syncytial virus
(RSV); given albuterol nebulization and sent home with albuterol by metered-dose inhaler (MDI) with mask spacer; did not
require supplemental O2, antibiotics, or intravenous (IV) fluids
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| Course at home: continued to wheeze daily; some coughing; some improvement with albuterol; wheezing inaudible
when asleep; no dysphagia or emesis; occasional sneezing; sometimes “a little blue around the lips” after prolonged crying
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| Additional history: family history positive for asthma and eczema, but no cystic fibrosis (CF) or other genetically related
pulmonary diseases; no pets and no environmental tobacco smoke; family thought child lactose-intolerant, but steatorrhea
absent; no snoring or stridor; voice usually normal; growth and development normal
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| Differential diagnosis: asthma; CF; bronchopulmonary dysplasia; chronic lung disease; reflux with aspiration; congenital
anomalies, eg, tracheomalacia, vascular ring; foreign body
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| Treatment: fluticasone (44 µg by MDI, 2 puffs bid); albuterol by MDI, 2 puffs prn; patient showed minimal improvement
and had increased difficulty feeding; remained happy and active
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| Further work-up: repeat chest x-ray (showed possible mild peribronchial thickening); esophagography (showed no aspiration,
gastroesophageal reflux [GER], or vascular ring); flexible bronchoscopy (identified laryngotracheobronchomalacia);
mucosa appeared friable
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| Case diagnosis: wheezing caused by dynamic airway collapse due to tracheomalacia; not always clear this is sole explanation
for wheezing; possible wheezing more prolonged because of previous RSV infection
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| Clinical clues to tracheomalacia: happy wheezer; sporadic wheezing; sometimes difference with change in position
(frequently, difference with activity vs quiet); onset at early age; suboptimal response to acute bronchodilators (sometimes
become worse); almost all children with tracheomalacia improve over time; bronchomalacia more problematic
(many patients require O2 when young); not clear whether bronchomalacia outgrown as with laryngomalacia and tracheomalacia
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| Diagnosis of CF: predominant clinical findings—respiratory symptoms (45%); meconium ileus in newborn period
(15%); sibling with diagnosis of CF (8%); gastrointestinal (GI) symptoms (32)%; caveats—CF common in whites; 10%
to 15% of patients pancreatic sufficient (no failure to thrive [FTT]); nearly as common in Hispanics; sweat test—
inexpensive but not easy (requires experienced laboratory); confirm diagnosis with genotyping
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| Diagnosis of asthma in small children: clinical symptoms include cough, wheezing, and dyspnea; most common trigger
in early childhood viral upper respiratory tract infection; usually positive response to bronchodilators or steroids; supportive
evidence includes personal or family history of asthma or atopy; recurrence; chest x-ray findings (normal or peribronchial
thickening); careful assessment of differential diagnosis recommended
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| MDI vs nebulizer: if used properly, both delivery systems work, even in infants and toddlers; when making selection,
consider equipment already in home and parents’ comfort
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| Management of infant wheezer: diagnosis—do careful and detailed history and examination; remember asthma
can start in infancy; separate intermittent from chronic lung disease; look for aggravating and alleviating factors; careful
exploration of associations can provide clues to diagnosis; if asthma suspected, treat based on severity of disease; work-
up—tailor to most likely diagnosis; careful follow-up and review of progress of empiric therapy; step-wise increase in
testing if patient unresponsive; diagnostic tests—include complete blood count (CBC), chest x-ray, immunoglobulins,
sweat test, evaluation for allergies, purified protein derivative (PPD), esophagoscopy or other test for reflux (also excludes
vascular ring); bronchoscopy; computed tomography (CT)
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| SUDDEN INFANT DEATH SYNDROME (SIDS) AND INFANT APNEA —Miles Weinberger, MD, Professor of Pediatrics
and Director, Pediatric Allergy and Pulmonary Division, University of Iowa College of Medicine, Iowa City
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| Sudden infant death syndrome: unexplained death in previously healthy infant; diagnosis requires complete autopsy,
examination of death scene, and review of clinical history
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| Pathologic and clinical correlates of sudden death in infants: diagnosis based on unexplained death of infant
<1 yr of age (usually <6 mo of age); findings at investigation or autopsy, eg, evidence of recent viral respiratory infection,
may not explain death; may find evidence of abuse, neglect, maternal drug abuse, even mild bronchopneumonia; variety
of metabolic disorders associated with sudden death in infants; however, these infants not previously healthy
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| Epidemiology of SIDS: occurs at 1 to 6 mo of age (85% at 2-4 mo); most common cause of death during first year of
life (beyond neonatal period); rate of occurrence 1 in 400 in past but has changed; very low rates in Japan and China;
highest reported rates until recently in New Zealand; in United States, rates vary with ethnic group (highest in American
Indians, lowest in Asians)
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| Risk factors: infant—prematurity; low Apgar scores; bronchopulmonary dysplasia (BPD); multiple births; previous
acute life-threatening events (ALTEs); sibling with SIDS; maternal—smoking; drug abuse; age <20 yr; co-sleeping;
environmental—passive smoke exposure; bundling or overheating; soft bedding; prone sleeping position; other—
ethnicity; socioeconomic status; cultural influences; possible genetic factors—concordance in twins; increased incidence
in subsequent births; increased frequency observed in some families (5-fold increased risk in siblings in US population
as whole, but virtually no increased risk in siblings in middle class families); some diagnoses of familial SIDS
subsequently shown to be homicides
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| Prone sleeping position: supine sleeping usual in Asia (lowest incidence of SIDS); prone sleeping usual in New
Zealand Maoris (very high incidence of SIDS; also tend to sleep on soft bedding); 50% decrease in SIDS reported in Australia,
England, and Seattle, WA, after widespread publicity encouraging supine sleeping; prone sleeping synergistic with
overheating and soft bedding; possible explanations—decreased inhaled fraction of inspired oxygen (FiO2) and increased
inhaled CO2 seen in prone infants (particularly with soft bedding); during first few months after birth, infants obligate
nose breathers and have increased compressibility of nasal cartilage; many infants have decreased hypoxic arousal
and ventilatory response to CO2 between 1 and 6 mo of age
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| Face positions in prone sleeping: study compared face-down position to face to side; findings—inspired CO2 consistently
greater during face-down position; effect greatly accentuated with soft bedding; O2 saturation and end-tidal
CO2—O2 saturation 85% with face down, 96% with face-to-side; end-tidal CO2 elevated with face down, normal with
face-to-side
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| Decreased arousal from sleep in SIDS: 16 infants who had sleep studies weeks before SIDS death compared to
controls; findings—incomplete arousal processes in infants who subsequently died of SIDS
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| Prevention of SIDS: supine sleeping; avoidance of exposure to tobacco smoke; avoidance of overheating and soft bedding
and pillows; use of pacifier; evidence overwhelming that combination of decreased arousal (developmental) and
prone sleeping responsible for SIDS
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| Apnea: transient respiratory pauses (all infants have some cessation of respiration; pathologic apnea defined as pauses ≥20
sec); apnea of prematurity—multiple episodes per day; common in small premature infants; responsive to xanthines; apnea
of infancy—sporadic episodes; central, obstructive, or mixed; rarely (if ever) precursor of SIDS; may be associated
with treatable pathology; central apnea—20 sec of apnea (no respiratory effort); no bradycardia, hypoxemia, or hypercapnea;
benign; periodic breathing—3- to 10-sec pauses in breathing, interrupted by respiratory efforts <20 sec; gradual
decrease in oxygenation; self-limited immature breathing pattern; not predictive of SIDS; obstructive apnea —30 sec of
apnea; respiratory effort persists; some slowing of heart rate; no hypoxemia or hypercapnea; benign; not predictive of
SIDS; due to abnormalities of muscles of upper airway; can be caused by large tonsils and neuromuscular problems; not
risk for SIDS
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| Apnea of infancy: evaluation—history suggestive of aspiration or seizure; physical examination for upper airway obstruction;
pulse oximetry; electrolytes; chest x-ray; sepsis evaluation if warranted; home monitoring—indicated for rare
patient whose apnea episode associated with true ALTE; secondary indication parental anxiety; well-defined end point
for monitoring discussed with family in advance; should not continue past 6 mo of age
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| I NFLAMMATION AND CYSTIC FIBROSIS —Jeffrey S. Wagener, MD, Professor of Pediatrics, University of Colorado
School of Medicine, Denver
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| Pathophysiology of cystic fibrosis: defective gene leads to defective transmembrane regulator (CFTR) protein (surface
protein responsible for transmitting chloride across cell membrane; also found in mucus-secreting glands), resulting
in abnormal airway surface environment; also affected by modifier genes and by environment, eg, tobacco smoke; airway
obstruction, infection, and inflammation result; inflammatory reaction appears to result in long-term damage to airway
and bronchiectasis; bronchoalveolar lavage (BAL) cytology in infants without CF shows predominant cell alveolar
macrophage; in those with CF, predominant cell neutrophil
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| Inflammation in CF patients with stable clinically mild lung disease: study separated patients ≥14 yr of age
into those with >60% predicted lung function and those with >80% predicted lung function; compared to adult controls;
demonstrated that total cells and percentage of neutrophils significantly different; so even with mild disease, patients
could have significant airway inflammation
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| Inflammation in infants with CF: study looked at infants <2 yr of age, comparing control group to patients with CF and
negative culture from BAL fluid (BALF), and patients with CF and positive culture from BALF; greater number of neutrophils,
increased proinflammatory cytokine (interleukin-8 [IL-8]), and elevated free elastase seen in patients with CF and airway
infection; free elastase causes damage that leads to bronchiectasis
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| BALF inflammatory response in CF: study compared uninfected and infected control populations to CF patients
with and without positive BALF cultures; demonstrated that inflammation in CF neutrophil-dominant inflammatory response
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| Change in BALF neutrophil elastase activity over time: study using annual bronchoscopy in infants with CF
found that if culture of BALF negative, neutrophil elastase activity low; if culture negative on repeat bronchoscopy, activity
stayed low, but if positive on second bronchoscopy, elastase increased; if culture positive at first, then negative
later, elastase remained elevated; patients with repeatedly positive cultures had persistently elevated elastase
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| Tobramycin solution for inhalation (Infant TOBI study): evaluated microbiologic response to inhaled antibiotic;
patients 3 mo to 6 yr of age and clinically stable; had upper airway cultures positive for Pseudomonas aeruginosa
twice over 6-mo period; at baseline bronchoscopy, 50% negative for P aeruginosa in lower airway; conclusions—
inflammation occurs with positive and negative lower airway cultures; repeatedly positive upper airway cultures usually
predictive of lower airway inflammation
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| Sputum induction in children with CF: study found that by 11 yr of age, nearly 50% of patients could spontaneously
produce sputum, but at <11 yr of age, only small percentage could do so; sputum induction—subjects inhaled hypertonic
saline (3%) over 12 min; every few minutes, patients coughed and expectorated as much as possible; O2
saturation and pulmonary function monitored; conclusions—sputum induction relatively safe and produces adequate
quantities for analysis; in CF patients, spontaneously produced as well as induced sputum different from sputum induced
in normal controls and reflects CF pathophysiology, ie, corroborates findings of bronchoscopy studies; induced sputum
indices correlate with pulmonary function
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| Induced sputum: study of CF patients >6 yr of age hospitalized for pulmonary exacerbation; patients treated for ≥9
days; sputum induction performed at start and end of hospitalization (within 2 days of completing antibiotics); pulmonary
function tests improved; bacteria counts fell; IL-8 and free elastase decreased, but percent neutrophils remained high
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| Inflammatory markers from sputum: azithromycin—180 subjects; CF patients >6 yr of age; received 6 mo of
oral azithromycin or placebo; sputum free elastase increased in placebo group but not in azithromycin group; interferon
gamma-1B (Actimmune)—65 CF patients >12 yr of age received 3 mo of interferon gamma-1B or placebo; sputum free
elastase increased in placebo but not in Actimmune group; conclusions—sputum elastase increases over time in untreated
CF patients; changes in sputum inflammatory markers may relate to bacterial density in sputum
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| Therapies that may affect airway inflammation in CF: hypertonic saline (targets abnormal airway surface environment;
hydration brings improvement); dornase alpha (effective against airway obstruction); TOBI and IV antibiotics
effective in decreasing infection; multiple therapies effective in reducing inflammation; lung transplantation may improve
survival in patients with bronchiectasis
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Educational Objectives
| The goal of this activity is to provide listeners with a better understanding of some of the challenges of the pediatric airway.
After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Evaluate the wide differential diagnosis for wheezing babies.
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| 2. List key historical and examination points for targeting the evaluation and management of the wheezing infant.
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| 3. Cite the epidemiology and risk factors for sudden infant death syndrome (SIDS), and describe possible reasons for
the association between SIDS and prone sleeping.
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| 4. Recognize the characteristics of the different forms of infant apnea, and perform an effective evaluation of the patient
with apnea of infancy.
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| 5. Describe some of the characteristics of airway inflammation in cystic fibrosis (CF) learned from recent clinical studies.
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Discussed on This Program
Albuterol (salbutamol sulphate in United Kingdom) [AccuNeb, Proventil, Proventil HFA, Proventil Repetabs, Ventolin,
Ventolin HFA, Volmax]
Azithromycin [Zithromax, Zmax]
Dornase alfa (recombinant human deoxyribonuclease; DNase) [Pulmozyme]
Fluticasone propionate [Cutivate, Flovent, Flovent HFA, Flovent Diskus, Flovent Rotadisk, Flonase]
Interferon gamma-1B [Actimmune]
Levalbuterol HCl [Xopenex, Xopenex HFA]
Prednisone [Deltasone, Liquid Pred, Meticorten, Orasone, Panasol-S, Prednicen-M, Prednisone Intensol Concentrate,
Strerapred DS]
Tobramycin sulfate [AKTob, Defy, Nebcin, Nebcin Pediatric, TOBI, Tobramycin Sulfate Pediatric, Tobrex]
Suggested Reading
American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome: The changing concept
of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables
to consider in reducing risk. Pediatrics 116:1245, 2005; Hauck FR et al: Do pacifiers reduce the risk of sudden
infant death syndrome? A meta-analysis. Pediatrics 116:e716, 2005; Jones MA, Wagener JS: Managing acute pediatric
asthma: keeping it short. J Pediatr 139:3, 2001; Khan TZ et al: Early pulmonary inflammation in infants with cystic
fibrosis. Am J Respir Crit Care Med 151:1075, 1995; Konstan MW et al: Bronchoalveolar lavage findings in cystic fibrosis
patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care
Med 150:448, 1994; Martinez FD et al: Asthma and wheezing in the first six years of life. The Group Health Medical
Associates. N Engl J Med 332:133, 1995; McKenna JJ, McDade T: Why babies should never sleep alone: a review of
the co-sleeping controversy in relation to SIDS, bedsharing and breast feeding. Paediatr Respir Rev 6:134, 2005; Morgan
WJ et al: Outcome of Asthma and Wheezing in the First 6 Years of Life: Follow-up through Adolescence. Am J
Respir Crit Care Med 172:1253, 2005; Muhlebach MS et al: Quantitation of inflammatory responses to bacteria in
young cystic fibrosis and control patients. Am J Respir Crit Care Med 160:186, 1999; Rothman KJ, Wentworth CE
3rd: Mortality of cystic fibrosis patients treated with tobramycin solution for inhalation. Epidemiology 14:55, 2003; Sagel
SD et al: Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. Am J
Respir Crit Care Med 164:1425, 2001; Sagel SD et al: Induced sputum inflammatory measures correlate with lung
function in children with cystic fibrosis. J Pediatr 141:811, 2002; Saiman L et al: Macrolide Study Group. Azithromycin
in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.
JAMA 290:1749, 2003; Saiman L et al: Macrolide Study Group. Heterogeneity of treatment response to azithromycin
in patients with cystic fibrosis. Am J Respir Crit Care Med 172:1008, 2005; Slattery DM et al: CF: an X-ray database
to assess effect of aerosolized tobramycin. Pediatr Pulmonol 38:23, 2004; Spitzer AR: Current controversies in the
pathophysiology and prevention of sudden infant death syndrome. Curr Opin Pediatr 17:181, 2005; Wagener JS et al:
Early inflammation and the development of pulmonary disease in cystic fibrosis. Pediatr Pulmonol Suppl 16:267, 1997;
Weinberger M: Airways reactivity in patients with CF. Clin Rev Allergy Immunol 23:77, 2002; Weinberger M:
Corticosteroids for first-time young wheezers: current status of the controversy. J Pediatr 143:700, 2003; Weinberger
M, Ahrens R: Oral prednisolone for viral wheeze in young children. Lancet 363:330, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Wagener is an employee of and a stockholder in Genentech, Inc.
Drs. Stillwell, Weinberger, and Wagener were recorded at Masters of Pediatrics: Contemporary and Future Pediatrics,
held January 29-30, 2006, in Bar Harbour, FL, and sponsored by the University of Miami Miller School of Medicine. The
Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
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