ASTHMA MANAGEMENT/SLEEP DISORDERS
| CONTROVERSIES IN ASTHMA MANAGEMENT —Thomas Stibolt, MD, Clinical Associate Professor of Medicine,
Oregon Health and Science University, and Senior Physician, Pulmonary and Critical Care Medicine, Northwest Kaiser
Permanente, Portland
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| Role of leukotriene modifiers: 5-lipoxygenase inhibitors (eg, zileuton) or cysteinyl leukotriene receptor antagonists (eg,
zafirlukast [Accolate], montelukast [Singulair]); reasonable controllers of persistent asthma but not first-line medications;
findings of 2004 Cochrane review of literature—in all trials, antileukotriene agents less effective than inhaled
corticosteroids (ICS) in controlling asthma; use of antileukotrienes resulted in 65% increased risk for exacerbation requiring
systemic steroids; overall, combining long-acting β-agonist (eg, salmeterol) with ICS more effective than adding
antileukotriene (eg, montelukast)
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| Peak flow monitoring: third version of National Asthma Education and Prevention Program (NAEPP) guidelines recommended
ongoing peak flow monitoring in patients with persistent asthma; recommendation based on indirect evidence;
however, clinical experience shows that most patients do not continue peak flow monitoring; keep in mind that—proper
measurements require recording best of 3 efforts made on awakening, before taking bronchodilator; prediction equations
for peak flow based on population norms not very helpful; best to use patient’s personal best determined over 2 wk of
continuous peak flow measurement (value <80% of personal best indicates problem); patient must use same peak flow
meter over time
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| Asthma control: requires measures to—prevent chronic and troublesome symptoms; maintain normal or near-normal
pulmonary function tests (PFTs); prevent recurrent exacerbations; minimize side effects (real and perceived); meet expectations
for and satisfaction with care
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| Indicators of poor asthma control: before increasing patient’s medications, check—his or her smoking status; inhaler
technique; adherence to prescribed regimen; environmental changes (eg, mold; new house; new carpets; paint); consider
alternative diagnosis
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| Control issues: national studies have shown asthma to be uncontrolled problem at individual and population levels; recent
increases in knowledge of pathophysiology and therapy have not changed patient outcomes; guidelines have not proven
helpful in improving asthma management
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| Spirometry: important at initial assessment (forced expiratory volume in 1 sec [FEV1 ] probably single best predictor of
short- and long-term pulmonary problems; in addition, good for determining whether patient has problem other than airflow
obstruction that may be confounding condition); do after treatment has stabilized symptoms or when major changes
in disease occur; recommended at least every 1 to 2 yr to evaluate patient’s status over time
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| Monitoring quality of life and functional status: periodically assess—amount of short-acting β-agonist used; work or
school missed due to asthma; changes in activity patterns due to asthma (eg, reduction in exercise); sleep disturbance
due to asthma or cough
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 | “Rule of 2s”: patient in trouble if—using quick-relief inhaler >2 times/wk; awakening at night with asthma or cough >2
times/mo; refilling albuterol prescription >2 times/yr
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| Adherence: studies show large proportion of patients with clear markers of uncontrolled or severe asthma who present to
emergency department (ED) with exacerbation not given prescription for ICS; study looking at patients who received
prescriptions found only 50% fill it, and of that group, much smaller percentage go on to refill prescription
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| Achieving adherence: interactive training recommended; includes education that teaches basic skills (eg, avoiding triggers;
proper use of medications), simplifies treatment regimen, and provides positive reinforcement; ongoing asthma-
management study looking at outcomes when patients allowed to share in treatment decision making (hope is that patients
involved in choosing therapy more likely to be adherent)
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| Monitoring pharmacotherapy: must monitor—patient adherence to regimen; inhaler technique; use of short-acting inhaled
β-agonist; need for oral corticosteroid burst therapy; side effects of medications
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| Assessing adherence: self-reports or daily diaries unreliable and not recommended; review pharmacy data; medication not
working important warning sign; adherence especially problematic with inhaled anti-inflammatory medications; not understanding
patient’s point of view and motivation can lead to greater adherence problems and loss of communication
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| ICS recommended by speaker: for many patients with asthma, QVAR formulation of beclomethasone excellent drug;
when beclomethasone ineffective, use budesonide or fluticasone
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| Uses of oral corticosteroids: for managing severe exacerbations; generally, start patient on 40 mg/day oral prednisone,
then keep him or her on dose until symptoms relieved, plus another 48 hr
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| Role of ICS in management of acute asthma attack (eg, in ED): probably reasonable to start ICS in ED, not to treat exacerbation,
but to get patient thinking about taking them; some weak evidence inhaled particles may slightly irritate airways;
advantage of systemic steroids is that they work much faster than ICS because dose much higher
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| ICS and risk for osteoporosis: with QVAR formulation of beclomethasone, risk probably so low as to be unimportant; if
giving fluticasone, refer patient for dual-energy x-ray absorptiometry (DEXA) scan
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| Should leukotriene modifiers be avoided? no; wonderful drugs and probably should be added third, after ICS and long-
acting β-agonists; just not first-line controllers; montelukast preferred due to once-daily dosing
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| Ipratropium, tiotropium (Spiriva), formoterol, and salmeterol in asthma management: generally, ipratropium and tiotropium
not good asthma drugs; salmeterol and formoterol long-acting β-agonists available in United States; similar in
onset of action; speaker does not use fomoterol because of poor design of inhaler
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| Use of pulmonary function testing guidelines for translating peak expiratory flow (PEF) into FEV1 : PEF and FEV1 do not
have good correlation; epidemiologically, FEV1 much better, more consistent measure of airflow obstruction; early on,
speaker does spirometry to establish presence of airflow obstruction; once patient on therapy and symptoms looking
better, he repeats spirometry to confirm improvement in airflow; if patient has problem, spirometry done some time after
exacerbation
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| Is use of β-agonists in association with exercise evidence of poor control? no; exercise asthma entity unto itself; short-acting
β-agonists and cromoglycates (cromolyn; nedocromil), which speaker generally finds useless in adults, can be helpful
in these patients and work fairly quickly (within 1-2 days); if patient using β-agonist only before exercise and not
needing it in evening or after awakening in morning, speaker ignores numbers of canisters used, unless >12 per year
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| Is ipratropium recommended β-agonist as first-line treatment of acute exacerbations? no; combination of ipratropium and
short-acting β-agonist recommended
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| Can short-acting β-agonist be combined with long-acting β-agonist? long-acting β-agonist has to be taken on regular
schedule (eg, twice daily); patients encouraged to use short-acting β-agonist only when needed for rescue; however, all
speaker’s patients on ICS and long-acting β-agonist also have canister of short-acting β-agonist (only thing that can reverse
exacerbation quickly enough to prevent trip to ED)
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| SLEEP MEDICINE FOR THE INTERNIST —Alejandro D. Chediak, MD, Associate Professor of Medicine and Chief,
Sleep Disorders Center, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida
|
| Restless legs syndrome (RLS): one of few sleep disorders that can be diagnosed in office without testing; treatment extremely
effective; International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria—desire to move
limbs (usually with paresthesias or dysesthesias); motor restlessness (eg, spontaneous flexion of legs and jerking motions);
symptoms worse at rest and relieved (partially or completely) with activity; generally occurs in both legs; can involve
arms (rare); symptoms worse at night (circadian rhythm); on polysomnography, patients show stereotypical
repetitive movements of lower extremities in way that disturbs sleep (not diagnostic; can occur independently of RLS)
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| Types of RLS: primary—no identifiable predisposing factor; familial trend (autosomal dominant trait; fairly high penetrance;
linked to chromosome 12q); does not present at any given age (however, unusual in children); secondary—more
common form; common in patients with iron deficiency anemia, uremia, pregnancy, neurologic lesions or syndromes
(eg, Parkinson’s disease), spinal cord injuries; can be induced or made worse by drugs (eg, selective serotonin reuptake
inhibitors [SSRIs]; tricyclic antidepressants (TCAs); lithium; dopamine blockers)
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| Role of iron in RLS: iron deficiency (particularly in cerebrospinal fluid [CSF]) important for development of RLS; iron
needed to make tyrosine hydroxylase, which is rate-limiting enzyme in dopamine production; RLS essentially dopamine-
deficiency state in central nervous system (CNS)
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| Differential diagnosis: neuropathy (most commonly, diabetic peripheral neuropathy; lumbar disc disease); depression
(RLS due to drugs, eg, SSRIs, used to treat depression); arthritis; peripheral vascular disease; akathisia
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| Laboratory evaluation of RLS: if patient presents with apparent RLS, only testing required is serum ferritin level and
screening for uremia and diabetes; referral to sleep laboratory unnecessary unless sleep apnea or other contributing factor
suspected; serum feritin — better marker of brain and CSF iron levels than serum iron, which can be normal in RLS; if
serum ferritin <50 µg/L, patients respond to iron
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| Treatment: dopaminergic medications—effect immediate; doses required very small; given 30 min before bedtime;
benzodiazepines—used in past; main benefit allowing patient to fall asleep; (do not have major effect on symptoms);
minor effect on periodic movements of legs seen in majority of patients when sleeping; opioids—can have beneficial effect
(directly enhance dopamine transmission in CNS); anticonvulsants used with some success in patients who have
variation of RLS associated with peripheral neuropathy; patient with serum ferritin <50 µg/L may respond to iron therapy
(effect not immediate; takes time to get CSF iron level high enough to cause relief of symptoms); speaker’s approach—
provides immediate relief with dopamine agonist while doing work-up for uremia, diabetes, other possible causes, and
serum ferritin test; if serum ferritin low, adds iron; after 1 mo, when iron level above threshold of 50 µg/L, attempts withdrawal
of dopamine agonist (if serum ferritin ≥50 µg/L, does not add iron)
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| Narcolepsy: syndrome, not disease; probably >1 defect; clinical presentation—excessive daytime sleepiness (EDS); cataplexy,
hypnagogic hallucinations, and sleep paralysis (dissociated rapid eye movement [REM] sleep phenomena); clinical
features of cataplexy—muscle weakness triggered by emotions (eg, laughter; happiness; excitement; anger);
typically of short duration (≈5 min); patients generally maintain consciousness during cataplectic episodes (may have visual
hallucinations)
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| Hypocretin in narcolepsy: research in animal models has shown narcolepsy with cataplexy is defect in hypocretin neurotransmission
system; patients who have narcolepsy with cataplexy almost always have absent or nearly absent hypocretin-1
in CSF (on autopsy, generally have deficiency of hypocretin cells in hypothalamus); patients with narcolepsy who
are hypocretin deficient (and thus more likely to have cataplexy) almost always type positive for HLA-DQB10602
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| Diagnosis of narcolepsy: in office (with patient complaint of EDS plus witnessing of cataplexy); by polysomnography and
multiple sleep latency test (MSLT) if cataplexy not witnessed (majority of cases); by assay of CSF hypocretin, given right
clinical syndrome (ie, EDS and symptoms suggestive of cataplexy)
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| Therapeutic approach: treatment of sleepiness (alertness-promoting drugs); when present, treatment of dissociated REM
sleep phenomena, particularly cataplexy (SSRIs and TCAs of value); sodium oxybate now drug of choice (highly effective
in controlling cataplexy)
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| Sleep-disordered breathing (SDB), metabolic syndrome, and cardiovascular health: recently established that untreated
SDB associated with hypertension and cardiovascular disease (CVD); SDB has role in metabolic syndrome
(which in turn has role in atherosclerosis, CVD, and stroke)
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| Confirmed SDB and metabolic dysfunction: analysis of 13 studies (1993-2003) showed SDB associated with glucose
intolerance and insulin resistance in dose-dependent fashion; lack of O2 often predicted insulin resistance; frequency of
events (ie, apnea/hypopnea index [AHI]) and lack of O2 both significantly associated with glucose intolerance and isolated
insulin resistance
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| Prevalence of SDB and metabolic abnormalities: 50% of patients with mild-to-moderate SDB present with glucose intolerance
and/or insulin resistance (without frank diabetes); dose-response curve between increase in AHI and worsening
insulin resistance
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| Treatment of SDB: study of patients with SDB and abnormalities of metabolism found that, within 2 days of initiating
therapy with continuous positive airway pressure (CPAP), indices of abnormal metabolism and insulin sensitivity improved
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| Role of SDB in metabolism: example of obese patient who is insulin resistant and who may also have SDB; SDB produces
hypoxia and sleep loss; which leads to oxidative stress, which in turn causes vascular inflammation and endothelial
dysfunction, facilitating abnormal circulatory events; hypoxia and sleep loss activate sympathomimetic system, which
activates catecholamine release and alters glucose metabolism, leading to hyperinsulinemia and insulin resistance; also
known that untreated SDB produces hypercytokinemia which can by itself produce EDS or insulin resistance; EDS leads
to inactivity; inactivity transfers back into obesity; inactivity itself (independent of obesity and SDB) can also produce insulin
resistance
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Educational Objectives
| The goal of this activity is to provide listeners with a better understanding of some of the controversies in asthma management
and an update on sleep disorders. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Explain the role of leukotriene modifiers (including their efficacy and possible disadvantages) and employ them in
the management of persistent asthma.
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| 2. Describe the uses of and indications for peak flow monitoring and spirometry in the evaluation of patients with
asthma.
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| 3. Name the elements of asthma control, recognize indicators of poor asthma control, and work to achieve patient adherence
to therapy.
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| 4. Diagnose and effectively treat patients with restless legs syndrome (RLS) or narcolepsy.
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| 5. Explain the relationship between untreated sleep disordered breathing (SDB) and the metabolic syndrome.
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Discussed on This Program
Albuterol (salbutamol sulphate in United Kingdom) [AccuNeb, Proventil, Proventil HFA, Proventil Repetabs, Ventolin,
Ventolin HFA, Volmax]
Beclomethasone dipropionate [Beconase, Beconase AQ, QVAR, Vancenase, Vancenase AQ 84 mcg, Vancenase
Pockethaler, Vanceril, Vanceril Double Strength]
Budesonide [Entocort EC, Pulmicort Respules, Pulmicort Turbuhaler, Rhinocort, Rhinocort Aqua]
Carbidopa [Lodosyn]
Cromolyn sodium (disodium cromoglycate) [Crolom, Gastrocrom, Intal, NasalCrom, Opticrom]
Fluticasone propionate [Cutivate, Flovent, Flovent Diskus, Flovent Rotadisk, Flonase]
Formoterol fumarate [Foradil Aerolizer]
Gabapentin [Neurontin]
Ipratropium bromide [Atrovent]
Levodopa (L -dopa) [Dopar, Larodopa]
Lithium [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs]
Montelukast sodium [Singulair]
Nedocromil sodium [Alocril, Tilade]
Pranlukast [Ultair] (not available in United States)
Prednisolone [AK-Pred, Delta-Cortef, Econopred, Econopred Plus, Inflamase Forte, Inflamase Mild, Orapred, Pred Forte,
Pred Mild, Prednisolone Acetate Ophthalmic, Prelone]
Prednisone [Deltasone, Liquid Pred, Meticorten, Orasone, Panasol-S, Prednicen-M, Prednisone Intensol Concentrate,
Strerapred, Strerapred DS]
Ropinirole HCl [Requip]
Salmeterol xinafoate [Serevent Diskus]
Sodium oxybate [Xyrem]
Tiotropium bromide [Spiriva, Spiriva HandiHaler]
Zafirlukast [Accolate]
Zileuton [Zyflo]
Suggested Reading
Capra V, Rovati GE: Leukotriene modifiers in asthma management. IDrugs 7:659, 2004; Dauvilliers Y et al: Clinical aspects
and pathophysiology of narcolepsy. Clin Neurophysiol 114:2000, 2003; Ducharme FM: Inhaled corticosteroids versus
leukotriene antagonists as first-line therapy for asthma: a systematic review of current evidence. Treat Respir Med 3:399,
2004; Fujiki N et al: Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs
and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep 26:953, 2003; Fuller DE et
al: The Xyrem risk management program. Drug Saf 27:293, 2004; Hallstrand TS, Henderson WR Jr: Leukotriene modifiers.
Med Clin North Am 86:1009, 2002; Happe S: Excessive daytime sleepiness and sleep disturbances in patients with
neurological diseases: epidemiology and management. Drugs 63:2725, 2003; Hyland ME, Stahl E: Asthma treatment
needs: a comparison of patients' and health care professionals' perceptions. Clin Ther 26:2141, 2004; Itin I, Comella CL:
Restless legs syndrome. Prim Care 32:435, 2005; Jones C et al: Adherence to prescribed treatment for asthma: evidence
from pharmacy benefits data. J Asthma 40:93, 2003; Kakar RS, Kushida CA: Ropinirole in the treatment of restless legs
syndrome. Expert Rev Neurother 5:35, 2005; Kanbayashi T et al: CSF hypocretin measures in patients with obstructive
sleep apnea. J Sleep Res 12:339, 2003; Krahn LE: Sleep disorders. Semin Neurol 23:307, 2003; Luskin AT: Achieving
asthma control: the need for risk assessment. Manag Care 14:12, 2005; Mignot E: Sleep, sleep disorders and hypocretin (orexin).
Sleep Med 5 Suppl 1:S2, 2004; Mignot E et al: On the value of measuring CSF hypocretin-1 in diagnosing narcolepsy.
Sleep 26:646; 2003; National Asthma Education and Prevention Program: National Asthma Education and Prevention
Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics--2002. J
Allergy Clin Immunol 110:S141, 2002; O'Keeffe ST: Iron deficiency with normal ferritin levels in restless legs syndrome.
Sleep Med 6:281, 2005; Punjabi NM et al: Sleep-disordered breathing and insulin resistance in middle-aged and overweight
men. Am J Respir Crit Care Med 165:677, 2002; Punjabi NM et al: Sleep-disordered breathing, glucose intolerance, and
insulin resistance. Respir Physiol Neurobiol 16:136, 2003; Ram FS, Cates CJ, Ducharme FM: Long-acting beta2-agonists
versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev
25:CD003137, 2005; Simon RA: Clinical implications of combination therapy on the future of asthma management. Allergy
Asthma Proc 24:91, 2003; Storms WW: Review of exercise-induced asthma. Med Sci Sports Exerc 35:1464, 2003; Weinstein
AG: Should patients with persistent severe asthma be monitored for medication adherence? Ann Allergy Asthma Immunol
94:251, 2005.
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. For this issue, the faculty reports
nothing to disclose.
Dr. Stibolt spoke at Topics and Advances in Internal Medicine, held March 3-9, 2005 in San Diego, and sponsored by the
University of California, San Diego, School of Medicine. Dr. Chediak was recorded at the 40th Annual Postgraduate Course:
Internal Medicine Update 2005, held January 30 to February 4, 2005, in Miami Beach, Florida, and sponsored by the University
of Miami School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in
the production of this program.
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