Beginning in September, our Pediatric Grand Rounds resumed for the academic year. After many years of dedicated service as coordinator of Grand Rounds, Dr. Virginia Tucker has stepped down and Dr. Lisa Gilmer has assumed this responsibility. The presentations are at 8 a.m. on Friday mornings. The monthly schedules are available from the office of continuing education, 913-588-4438. The schedule is also available on our web site, www2.kumc.edu/kids/
This time of year is interview time for residency applicants for the pediatrics and medicine/pediatrics training programs. We have many outstanding applicants from our region as well as other parts of the nation. We look forward to an outstanding group of new recruits.
Happy Holidays,
Professor and Chair
Cystic fibrosis (CF), is an autosomal recessive disorder, affecting approximately 30,000 people in the United States. The U.S. Cystic Fibrosis Foundation reports that 1000 new cases are diagnosed annually, usually during infancy. An additional 3.3 percent of U.S. Caucasians are estimated to be symptom-free carriers of the CF gene. CF occurs with frequency of one in 2500 white, one in 17,000 African-American, one in 9500 Hispanic, and one in 11,200 Native American live births.
The CF gene was discovered in 1989 on the long arm of chromosome 7. Over 700 mutations of this gene have been identified. In the U.S., mutations at position 508 or homozygosity for delta 508 account for 70 percent of cases. The product of the CF gene, cystic fibrosis transmembrane conductance regulator, leads to impaired transepithelial movement of fluid and electrolytes.
The presentation of CF may include meconium ileus and intestinal obstruction at birth (5 to 10 percent), failure to thrive, pancreatic insufficiency (85 percent), nasal polyps, and lower respiratory tract infections. In addition, patients are at increased risk for heatstroke due to excessive salt loss with sweating, and for sterility due to the absence of the vas deferens. The diagnosis of CF is confirmed in the presence of the classical symptoms plus either a positive pilocarpine sweat chloride test (> 16 mEq per liter) or two mutations of the CF gene.
Median survival of CF is 30 years, with more than 90 percent of deaths due to lung disease. Thick mucus and impaired mucociliary clearance predispose to repeated infections, resulting in bronchitis, bronchiectasis, frequent pulmonary exacerbations, and eventual respiratory failure. Complications include hemoptysis and pneumothorax. Bacterial colonization occurs with Staphylococcus aureus or nonspecific Haemophilus influenzae at as early as 3 months of age, followed by Pseudomonas aeruginosa, which develops in 80 percent of patients by adolescents. Another common agent, Burkholveria cepacia results in chronic infection in 20 percent of patients. More frequently, however, this is associated with rapid deterioration leading to death within weeks to months.
Primary therapeutic interventions for CF patients are pancreatic enzymes, supplementation of vitamins A, D, E, and K, and proper nutrition with supplementation of fats and highly caloric foods. Pulmonary interventions include the use of bronchodilators in conjunction with physiotherapy, and possibly even mechanical percussion vests. Anti-inflammatory medications, including high dose ibuprofen (20 to 30 mg per kilogram per day) are useful in the younger population, with steroids offering benefit during acute exacerbation. Pulmozyme, a recombinant DNAse mucolytic agent, helps to reduce pulmonary exacerbations and need for hospitalization. Antibacterial therapy is beneficial both as a suppressive therapy, which diminishes frequency of exacerbations and slows disease progression, and empirically with acute symptoms. The most common regimen is the combination of an aminoglycoside with a penicillin or cephalosporin for a three-week course. Fewer options exist for Pseudomonas aeruginosa infections. The US CF foundation recommends quinolones for patients of all ages for this infection. Inhaled or aerosolized anti-pseudomonal therapy has been used for many years for early treatment or suppressive therapy. They achieve high local concentration with minimal risk of systemic toxicity. The newest of these formulations is the aminoglycoside tobramycin (TOBI®). Clinical data show that high but variable sputum concentrations are achieved. This is associated with significant sustained improvement in lung function, decreased use of anti-pseudomonal antibiotics, and decreased hospitalizations. No hearing loss or renal toxicity is associated with the use of tobramycin, and resistance after 12 months of therapy has been shown to be no more frequent than with placebo.
The final therapeutic consideration for the CF patient is lung transplantation. As experience grows, this has been associated with greater success and longer survival rates. Unfortunately, this therapy remains greatly limited due to donor availability.
Director, Cystic Fibrosis Center.
Obstructive sleep apnea (OSA) has been studied extensively in the adult population yet is both a common and potentially life-threatening entity in pediatrics as well. Some studies estimate prevalence as high as 6 percent in children < 16 years of age.
Sleep disorder breathing often goes undetected by both parents and physicians. Children can have severe apnea yet have normal daytime function. Many, but by no means all, patients with OSA also have some neurologic or musculoskeletal condition. Frequently parents assume their children's sleep pattern is normal for them or is just part of a constellation of symptoms from their underlying syndrome.
Common symptoms of OSA include persistent snoring, difficulty breathing during sleep, witnessed apnea, restless sleep, and mouth breathing. Less common symptoms include nausea, vomiting, enuresis, behavioral problems, and morning headaches. Unfortunately, many children with OSA go unrecognized until complications from severe long-standing hypoxia lead to failure to thrive, developmental delay, cor pulmonale, or respiratory failure. Sleep deprivation may also lead to poor neurologic function.
OSA results from pathophysiology of the upper airway. Airway patency depends on airway caliber as well as appropriately functioning oropharyngeal reflexes. As the airway obstructs, local reflexes respond by increasing upper airway muscular activity and tone in order to relieve the obstruction.
In children, these protective responses are not fully developed. Neuronal recruitment leading to increased upper airway muscle tone is sluggish. Also, respiratory control in children is dominated by inhibitory responses. The predominance of inhibitory responses during airway obstruction results in apnea rather than stimulation of respiration. Obstruction of the airway is more of a problem with sleep because oropharyngeal muscle tone is at its lowest during sleep. The majority of children with OSA do not appear to arouse in response to either upper airway obstruction, hypercapnia, or hypoxia and are able to maintain normal sleep architecture at the expense of oxygenation and hypercarbia. Thus a child with an adequate airway and no complaints of hypersomnolence during the day can still have significant OSA while asleep.
OSA can be seen in conditions that significantly increase negative intrathoracic pressure, such as laryngomalacia or large airway stenosis, resulting in dynamic airway collapse on inspiration. Structurally small airways, such as those seen in children with Downs syndrome or craniosynostosis as well as those with adenotonsillar hypertrophy, predispose patients to OSA. Children with congenital syndromes or malformation clearly comprise a significant number of patients with OSA and very often end up having recalcitrant apnea. Children with congenital cleft palate are at risk for OSA secondary to motor and sensory palatal dysfunction. Abnormal motor control of the cranial nerves in Arnold-Chiari syndrome can result in OSA as well. Additionally, generalized muscular hypotonia seen in patients with Downs syndrome and muscular dystrophy predisposed patients to airway obstruction. Those patients with poor connective tissue integrity, such as Marfan and Ehlers-Danlos syndrome, often demonstrate OSA. Lastly, children with achondroplasia may have both obstructive as well as central apnea. Central apnea arises from brain stem compression secondary to a small foramen Magnum while obstructive apnea results from small airway size and possible connective tissue abnormalities.
Physicians concerned about OSA should look for the following clues on exam. Remember, any degree of nasal obstruction, regardless of the cause, can contribute to OSA. Midface or mandibular hyperplasia as well as tonsillar hypertrophy are significant findings. Note that the size of the tonsils and adenoids clinically will not predict the degree of improvement in airway obstruction once they have been removed. The palate should specifically be examined for clefts and clues of submucosal clefts such is bifid uvula. The mobility of the palate should be noted as well. The increased work of breathing may exacerbate patients' OSA and their underlying parenchymal abnormalities would contribute to severe nocturnal hypoxia. Patients failing to thrive may have OSA as an etiology of their poor weight gain. Obesity in children is not strongly correlated with OSA though patients with OSA who are obese will have improvement of their apnea with weight loss.
After an overnight sleep study documents OSA, treatment is directed at the cause of obstruction. Nasal obstruction and excess secretions are addressed pharmacologically. Adenotonsillectomy is the mainstay of surgical treatment and is successful at treating a large majority of patients with OSA. Those patients with craniofacial malformations or achondroplasia will probably require ongoing treatment despite adenotonsillectomy. Those with surgical repair of their palate may actually have worsening of their OSA. Uvulopalatopharyngoplasty is generally not recommended in children. The use of BiPAP and CPAP can be successfully used and very young children as well as infants with the use of behavioral programs to introduce this therapy. Close follow-up by repeat sleep study or overnight oximetry is required as the child grows to document continued adequate treatment of the OSA.
Division Chief, Pediatric Pulmonology.
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