PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Asthma. Author manuscript; available in PMC 2013 October 31.
Published in final edited form as:
J Asthma. 2012 February; 49(1): 10.3109/02770903.2011.637599.
Published online 2011 December 1. doi:  10.3109/02770903.2011.637599
PMCID: PMC3813959
NIHMSID: NIHMS509309

Non-invasive testing of lung function and inflammation in pediatric patients with acute asthma exacerbations

Abstract

Objective

There is limited information on performance rates for tests of lung function and inflammation in pediatric patients with acute asthma exacerbations. We sought to examine how frequently pediatric patients with acute asthma exacerbations could perform non-invasive lung function and exhaled nitric oxide testing and participant characteristics associated with successful performance.

Methods

We studied a prospective convenience sample aged 5–17 years with acute asthma exacerbations in a pediatric emergency department. Participants attempted spirometry for percent predicted forced expiratory volume in 1-second (%FEV1), airway resistance (Rint) and exhaled nitric oxide (FENO) testing before treatment. We examined overall performance rates and the associations of age, gender, race, and baseline acute asthma severity score with successful test performance.

Results

Among 573 participants, age was (median [IQR]) 8.8 [6.8, 11.5] years, male 60%, African-American 57%, and Medicaid insurance 58%. Tests were performed successfully by [n (%)]: full ATS/ERS-criteria spirometry, 331 (58%); Rint, 561 (98%); and FENO, 354 (70% of 505 attempting test). Sixty-percent with mild-moderate exacerbations performed spirometry compared to 17% with severe exacerbations (P=0.0001). Participants ages 8–12 years (67%) were more likely to perform spirometry than those 5–7 years (48%) (OR=2.23, 95% CI: 1.45–3.11) or 13–17 years (58%) (OR=1.61, 95%CI: 1.00–2.59).

Conclusions

There is clinically important variability in performance of these tests during acute asthma exacerbations. The proportion of patients with severe exacerbations able to perform spirometry (17%) limits its utility. Almost all children with acute asthma can perform airway resistance testing, and further development and validation of this technology is warranted.

Keywords: Asthma, asthma exacerbation, spirometry, airway resistance, respiratory function testing

INTRODUCTION

Asthma is the most common chronic disease of childhood and the most frequent reason for childhood hospitalization in the United States.[2,5,25] Acute exacerbations account for almost two million emergency department (ED) admissions annually and an ED relapse rate of 7–15%.[26]

This complex genetic and environmental disease has great variability of clinical expression and response to treatment, and clinical evaluation can be difficult.[24] There are few objective measures to assess severity, and these are infrequently available in the ED environment. Acute severity scores may not correlate with the degree of functional lung impairment in pediatric patients with acute asthma exacerbations.[17] As a result there is variability in diagnosis and management and a lack of objective testing available to assess severity and response to treatment.[35]

Objective measurements of airflow obstruction (forced expiratory volume in 1-second, %FEV1), airway resistance (Rint), and inflammation (exhaled nitric oxide, FENO) have the potential to decrease this variability and to facilitate appropriate care of the pediatric patient with an acute asthma exacerbation. However, there is limited information on performance rates and patient characteristics associated with successful performance for these non-invasive measures.[7,10,17,23] Becker and colleagues and Kerem and colleagues enrolled only participants who could perform spirometry.[7,17] Langhan and Spiro examined performance rates for spirometry, defined as two acceptable forced vital capacity (FVC) maneuvers, amongst 36 children more than 6 years of age with asthma exacerbations, and found a 91% success rate.[23] We are not aware of studies examining Rint during acute asthma exacerbations in pediatric patients. Kwok and colleagues achieved a performance rate of 68% for FENO measurement amongst participants ages 2 to 18 years with acute asthma exacerbations.[22]

Our primary objective was to determine how frequently measurement of %FEV1, Rint and FENO could be successfully performed in patients ages 5 to 17 years with acute asthma exacerbations. We also examined associations of a priori designated participant characteristics (age, gender, race, and baseline acute asthma severity score) with successful test performance and the values of test measurements.

METHODS

Study Design, Setting and Selection of Participants

This observational study included 573 consecutive, unique participants enrolled in a parent study, the Acute Asthma Severity Assessment Protocol (AASAP).[6] AASAP is an ongoing prospective study of children ages 5 to 17 years with acute asthma exacerbations who present to an urban, academic pediatric emergency department (PED). Inclusion criteria were age 5 to 17 years, doctor-diagnosed asthma, signs or symptoms of an asthma exacerbation (cough, dyspnea, wheezing and/or chest pain),[34] need for treatment with systemic corticosteroid (CCS) and inhaled bronchodilator as determined by the attending physician, and availability for phone follow up (an AASAP requirement). We excluded participants with chronic lung disease other than asthma, foreign body aspiration, or other reason for pertinent signs and symptoms. The Institutional Review Board reviewed and approved this study protocol (#080058). Written informed consent of the parent and assent of the participant were obtained. The clinical team was not aware of test values and made all management decisions.

Methods of Measurement

At baseline, defined as after triage but before systemic CCS treatment, we recorded medical, family and social history and Global Initiative for Asthma (GINA) chronic asthma control for the preceding 3-months.[13] Other variables measured at baseline included the degree of breathlessness as determined by ability to speak (complete, short or partial sentences, words, or no speech) and the Pediatric Asthma Score (PAS, Table 1). The 15-point PAS was developed from expert consensus asthma management guidelines and has been used for approximately 15 years in our PED as the primary bedside measure to assess acute asthma severity.[29,32] The principle investigator (DHA) and research assistant (DJR) were trained by the device manufacturers and pediatric pulmonary function technicians in test performance.

Table 1
Asthma severity score in use during study period

Explanatory and Outcome Measures

Explanatory variables used to examine the associations of participant characteristics with successful test performance were determined a priori and included age, gender, race, and baseline PAS. We chose these variables because they are biologically plausible and readily obtained in all participants. The outcomes for these analyses were the ability to perform standardized airway resistance, exhaled nitric oxide and spirometry.

Airway resistance

Airway resistance was measured using a MicroDirect MRT6000 module (Micro Medical, Kent, England). A nose clip was applied and the participant was instructed to perform comfortable, tidal volume breathing through the mouthpiece (SpiroSafe, Micro Medical) and to keep the tongue against the floor of the mouth. We supported the submental tissue and cheeks and extended the neck slightly to achieve the ‘sniffing’ position.[15] Five measurements were made during exhalation and the median value recorded. The device outputs percent predicted values for participants aged 2 to 10 years using the McKenzie standards and absolute values (kPa/l/sec) for participants 11 years of age and above.[27]

Exhaled nitric oxide (FENO)

Exhaled nitric oxide, a measure of airway inflammation, was measured using a NIOX MINO Airway Inflammation Monitor (Aerocrine AB, Solna, Sweden). We instructed the participant to inhale through the device mouthpiece from residual volume to total lung capacity and to then exhale through the device at a steady flow rate. The device outputs user feedback with audible and light signals to enable the participant to exhale at an appropriate and steady flow rate.[3] This prevents contamination with nasal air by closing the velum. Measurement was made from a 6-second exhalation time.[21] Rint and FENO were measured before spirometry because the FVC maneuvers required for spirometry may alter airway tone and airway resistance measures.[8] The Rint and FENO measurement devices output results only after valid measurement maneuvers.

Spirometry

Spirometry was performed using a MicroDirect MicroLoop spirometer (Micro Medical, Kent, England). The spirometer was calibrated each morning with a 3-liter syringe. A nose clip was applied and the participant performed forced vital capacity (FVC) maneuvers in accordance with American Thoracic Society-European Respiratory Society (ATS/ERS) 2005 spirometry standards.[1,28] Knudson standards were used to calculate %FEV1.[19,36]

For each participant we attempted to obtain three FVC maneuvers meeting ATS/ERS acceptability criteria.[1,28] These include reproducibility criteria but note that “use of data from maneuvers with poor reproducibility is left to the discretion of the interpreter.” This is because patients with airways obstruction may have greater coefficients of variation and may not meet full reproducibility criteria.[31] Eliminating trials from these participants may result in systematic bias in the results reported.

Therefore, for participants who could not perform three FVC maneuvers that met full ATS/ERS criteria but who had at least one maneuver with flow-volume and volume-time curves meeting ATS/ERS criteria for start-of-test and end-of-test, a standing pulmonary function test oversight committee reviewed these trials to determine whether the results were “high-quality.” This committee is composed of a pediatric pulmonary function technician and a pulmonologist-pulmonary physiologist. Each member recorded their determination whether a non-ATS/ERS trial was high-quality based on the flow-volume and volume-time curves and spirometry calculations of the available FVC maneuvers. The members were blinded to the other member’s determination and to all other participant data. A trial was designated high-quality if both members determined independently made this assessment.

Statistical analysis

We included only first enrollment data for all analyses for participants with duplicate enrollments. Continuous variables are reported as means (standard deviation, SD) or medians [interquartile ranges, IQR], as appropriate and categorical variables as frequencies and proportions. Race and ethnicity were categorized in accordance with NIH guidelines.[30] We compared demographic characteristics of study participants with those of all patients ages 5 to 17 years admitted to the PED with a primary diagnosis of asthma exacerbation (ICD code 493). The Chi-square (χ2) test was used to examine differences in test performance proportions by age and by asthma severity groups. We used separate multivariable logistic regression models to assess the independent associations of the a priori determined predictor variables (age, gender, race, and baseline PAS) with performance of Rint, full ATS/ERS-criteria spirometry and FENO testing. To allow the testing of non-linear relationships of age with ability to perform each test, age was included as a flexible term using restricted cubic splines.[16] We also provide analyses for age groups (5–7, 8–12, and 13–17 years) based on mid- and late-childhood and adolescence, and for asthma severity (mild, moderate and severe). All analyses were performed using R version 2.10.1 software.[33]

RESULTS

Among 662 eligible patients approached for enrollment during the period April 7, 2008, to June 30, 2010, 640 provided informed consent and were enrolled, and 1 could not be contacted for phone follow up (an AASAP exclusion criterion), resulting in 639 participants with data available (Figure 1). Sixty-five patients had duplicate enrollments in this study during subsequent PED admissions. After excluding these, data from 573 unique participant enrollments were included for analyses.

Figure 1
Participant recruitment and study implementation

The demographic characteristics of participants were similar to those of the population ages 5 to 17 years admitted to the PED with a final diagnosis of acute asthma exacerbation (Table 2). Age (median [IQR]) of participants was 8.8 [6.8, 11.5], 60% were male and 57% African-American, 58% had Medicaid insurance, and presenting PAS score was 5 [2, 9]. Accessory muscle use was noted in 301 (52%) of participants. A greater proportion of participants aged 5 to 7 years (7.6%) had severe exacerbations than those aged 8 to 12 years (4.6%) or 13 to 17 years (0.9%) (P = 0.03, χ2). There were 130 (24%) participants admitted to hospital, with 38 (7%) admitted to the PICU. Reasons for hospitalization included inadequate ventilation in 103 (79%), hypoxia in 49 (38%) and social circumstances or need for asthma education in 85 (65%).

TABLE 2
Baseline demographic and asthma characteristics of participants with acute asthma exacerbations and of population aged 5 to 17 years with acute asthma admitted to pediatric emergency department during study period

Test performance rates and values for the entire cohort are presented in Table 3. Overall, 331 (58%) of participants performed spirometry meeting full ATS/ERS criteria (univariate analyses), and an additional 36 (6%) performed high-quality spirometry. Participants aged 8–12 (67%) years were more likely to perform spirometry than those aged 5–7 years (48%), or those aged 13–17 years (58%)), (P < 0.001, χ2). The proportion of participants with severe exacerbations (PAS 12 to 15) able to perform spirometry (17%) was less than the proportion with non-severe exacerbations (60%) (P < 0.001, χ2). In a multivariable logistic regression model, age remained associated with performance of ATS/ERS-criteria spirometry (P< 0.0001), whereas gender (P = 0.6), race (P = 0.78) and PAS severity as a continuous variable (P = 0.06) were not. Participants ages 8–12 years were more likely to perform spirometry than those 5–7 years (48%) (OR=2.23, 95% CI: 1.45–3.11) or 13–17 years (58%) (OR=1.61, 95%CI: 1.00–2.59). The non-linear association of age with ability to perform full ATS/ERS-criteria spirometry after adjustment for gender, race, and baseline acute asthma severity is depicted in Figure 2.

Figure 2
Predicted probability to perform ATS-criteria spirometry and exhaled nitric oxide with age adjusted for gender, race and acute asthma severity using multivariable logistic regression models.
TABLE 3
Performance success and overall values of tests of lung function and inflammation attempted by 573 unique participants aged 5 to 17 years with acute asthma exacerbations

Almost all participants with mild and moderate exacerbations and 86% of those with severe exacerbations could perform Rint testing (Table 3). No multivariable analyses were performed as 98% of participants could perform Rint testing. FENO testing was performed by 354 (70%) of the 505 who attempted the test and by the majority of participants with mild and moderate exacerbations. However, only 45% of participants in the 5 to 7 year age group and 29% with severe exacerbations could perform this test (P < 0.001, χ2). In a multivariable logistic regression model, performance of FENO testing was associated with age (P < 0.0001) and acute asthma severity (P = 0.0001), but not with gender or race. The non-linear association of age with ability to perform FENO in this model is depicted in Figure 2.

DISCUSSION

Many participants in this study were able to adequately perform noninvasive and objective tests of lung function and inflammation. However, there were differences in performance rates according to type of test, age group and acute asthma severity. The values obtained for Rint and %FEV1 in this cohort indicate significant lung function impairment. However, the median FENO value was normal, indicating that exacerbations in our cohort may have not resulted from eosinophilic airway inflammation.[4,18]

Although spirometry requires patient cooperation and coordination, tests meeting all ATS/ERS quality criteria was successfully performed by 58% of participants overall, with an additional 6% providing high-quality tests. Although few participants with severe exacerbations could perform spirometry testing (17%), the 60% with moderate episodes able to provide full ATS/ERS criteria studies is comparable to a prior study of peak expiratory flow measurement in a PED.[14] %FEV1 is the widely recognized criterion measure of asthma severity and, in contrast to peak flow measurement, the quality and variability of the forced vital capacity maneuvers are assessed. Attempts to perform this test may be warranted in the pediatric patient with an acute asthma exacerbation.

An unexpected finding was the greater proportion of participants ages 8 to 12 years (67%) who performed full ATS/ERS spirometry than did participants ages 13 to 17 years (58%) when adjusted for acute asthma severity, gender and race. This finding is consistent with investigations of child and adolescent willingness to participate in hypothetical, minimal-risk protocols, and with adolescents’ concerns over the “hassle” of participation.[9,37] This is a worthwhile area for quality improvement. Additionally, in multivariable analysis there was a non-significant trend toward an association of acute asthma severity with ability to perform spirometry (P = 0.06) that was driven by those with the greatest severity.

Airway resistance was performed successfully by almost all participants regardless of age or acute asthma severity. An alternate method of airway resistance measurement, impulse oscillometry, also requires only tidal breathing and passive patient cooperation and has been demonstrated to provide a valid and reproducible measure of lung function during exacerbations.[11,12,20] Our study results indicate the clinical practicality of tidal breathing methods of lung function testing during acute asthma exacerbations.

Seventy percent of participants were able to perform FENO testing, a proportion nearly identical to that noted by Kwok and colleagues.[22] Because this test requires a 6-second, coordinated expiratory maneuver, we anticipate that a greater proportion can perform this measure once an acute asthma exacerbation is at least partially controlled. The utility of FENO for acute asthma management in the emergency department environment is still unclear.[22]

The test values we observed in our cohort indicate clinically important decreases in lung function as determined by %FEV1 and Rint but essentially normal values for FENO. We believe that further study of Rint and FENO is warranted before they can be recommended for routine evaluation of acute asthma exacerbations in pediatric patients. In particular, further studies are needed of the validity of Rint and of normative values for patients greater than 10 years of age.

Our study has limitations. First, spectrum bias may be present because we used a convenience sample and did not recruit participants after 10PM. Spirometry, in particular, requires coordination and is effort dependent on the part of the participant, and we have found it difficult to obtain these studies late at night. In addition, we had sufficient time and resources with which to assist participants in performing these measurements, and clinicians may not have similar results in other settings. Finally, the order of testing (Rint, FENO, spirometry) may have affected the performance rates for FENO and spirometry, although Rint testing requires minimal effort.

Although our sample may not be representative of patients managed in other acute care settings, the demographic characteristics of our sample are comparable to the population of patients admitted to our PED with asthma exacerbations and include a broad spectrum of acute severity. In addition, our tertiary children’s hospital PED manages most pediatric patients with acute asthma in an urban, suburban and rural region. The full clinical variability of acute asthma can be difficult to precisely capture, yet we believe that our cohort represents a wide spectrum of both patient demographics and asthma presentations.

CONCLUSIONS

In conclusion, many pediatric patients with acute asthma exacerbations are able to perform non-invasive measures of lung function and inflammation. However, spirometry can only be obtained in approximately 60% of those with moderate and 17% of those with severe episodes, even under optimal circumstances in which a trained investigator has sufficient time to administer the study. This is a population in which a measure of lung function might meaningfully inform clinical decision making, yet spirometry has limited applicability and thus might not be the most appropriate measure of lung function during acute exacerbations.

Alternatively, measures of airway resistance that require only tidal breathing are more widely applicable and warrant further investigation in this population. These noninvasive and objective measures of lung function might improve assessment and management of acute asthma exacerbations by accounting for variability of clinical exacerbation expression, decreasing provider variability, and facilitating individual patient management. Future investigations are warranted to examine change of these lung function measurements during treatment and whether such change is predictive of need for hospitalization and other management decisions.

Acknowledgments

The authors gratefully acknowledge Donald J. Resha, EMT-P, for participant recruitment, and the nurses, respiratory therapists and staff of the Vanderbilt Children’s Hospital Emergency Department for their assistance.

Research support

This research was supported by the National Institutes of Health: [K23 HL80005-01A2] (Dr. Arnold); NIAID [K24 AI77930] (Dr. Hartert); and NIH/NCRR [UL1 RR024975] (Vanderbilt CTSA).

Footnotes

DECLARATION OF INTEREST STATEMENT

Aerocrine Corporation supplied the NIOX MINO nitric oxide monitor for this study. The authors have no other conflicts of interest to report.

References

1. Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society. Am Rev Respir Dis. 1991;144:1202–1218. [PubMed]
2. Asthma prevalence and control characteristics by race/ethnicity---United States, 2002. MMWR Morb Mortal Wkly Rep. 2004;53:145–148. [PubMed]
3. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171:912–930. [PubMed]
4. ATS Workshop Proceedings: Exhaled Nitric Oxide and Nitric Oxide Oxidative Metabolism in Exhaled Breath Condensate: Executive Summary. Am J Respir Crit Care Med. 2006;173:811–813. [PubMed]
5. American Lung Association. Trends in asthma morbidity and mortality. American Lung Association; New York: Jul 1, 2006. [Accessed January 18, 2007]. web site. Available at: http://www.lungusa.org.
6. Arnold DH, Gebretsadik T, Abramo TJ, et al. The Acute Asthma Severity Assessment Protocol (AASAP) study: objectives and methods of a study to develop an acute asthma clinical prediction rule. Emerg Med J. 2011 [PMC free article] [PubMed]
7. Becker AB, Nelson NA, Simons FE. The pulmonary index. Assessment of a clinical score for asthma. Am J Dis Child. 1984;138:574–576. [PubMed]
8. Black j, Baxter-Jones ADG, Gordon J, et al. Assessment of airway function in young children with asthma: comparison of spirometry, interrupter technique, and tidal flow by inductance plethsmography. Pediatr Pulmonol. 2004;37:548–553. [PubMed]
9. Brody JL, Annett RD, Scherer DG, et al. Comparisons of adolescent and parent willingness to participate in minimal and above-minimal risk pediatric asthma research protocols. J Adolesc Health. 2005;37:229–235. [PMC free article] [PubMed]
10. Commey JO, Levison H. Physical signs in childhood asthma. Pediatrics. 1976;58:537–541. [PubMed]
11. Delacourt C, Lorino H, Fuhrman C, et al. Comparison of the forced oscillation technique and the interrupter technique for assessing airway obstruction and its reversibility in children. Am J Respir Crit Care Med. 2001;164:965–972. [PubMed]
12. Delacourt C, Lorino H, Herve-Guillot M, et al. Use of the forced oscillation technique to assess airway obstruction and reversibility in children. Am J Respir Crit Care Med. 2000;161:730–736. [PubMed]
13. Global Initiative for Asthma POMC. Global strategy for asthma management and prevention. 7 A.D.
14. Gorelick MH, Stevens MW, Schultz T, et al. Difficulty in obtaining peak expiratory flow measurements in children with acute asthma. Pediatr Emerg Care. 2004;20:22–26. [PubMed]
15. Hadjikoumi I, Hassan A, Milner AD. Effects of respiratory timing and cheek support on resistance measurements, before and after bronchodilation in asthmatic children using the interrupter technique. Pediatr Pulmonol. 2003;36:495–501. [PubMed]
16. Harrell FE. Regression Modeling Strategies. New York: Springer; 2001.
17. Kerem E, Canny G, Tibshirani R, et al. Clinical-physiologic correlations in acute asthma of childhood. Pediatrics. 1991;87:481–486. [PubMed]
18. Kharitonov SA, Gonio F, Kelly C, et al. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J. 2003;21:433–438. [PubMed]
19. Knudson RJ, Slatin RC, Lebowitz MD, et al. The maximal expiratory flow-volume curve. Normal standards, variability, and effects of age. Am Rev Respir Dis. 1976;113:587–600. [PubMed]
20. Komarow HD, Myles IA, Uzzaman A, et al. Impulse oscillometry in the evaluation of diseases of the airways in children. Ann Allergy Asthma Immunol. 2011;106:191–199. [PMC free article] [PubMed]
21. Koopman M, Arets HG, Uiterwaal CS, et al. Comparing 6 and 10 sec exhalation time in exhaled nitric oxide measurements in children. Pediatr Pulmonol. 2009;44:340–344. [PubMed]
22. Kwok MY, Walsh-Kelly CM, Gorelick MH. The role of exhaled nitric oxide in evaluation of acute asthma in a pediatric emergency department. Acad Emerg Med. 2009;16:21–28. [PubMed]
23. Langhan ML, Spiro DM. Portable spirometry during acute exacerbations of asthma in children. J Asthma. 2009;46:122–125. [PubMed]
24. Lemanske RF, Jr, Busse WW. Asthma: clinical expression and molecular mechanisms. J Allergy Clin Immunol. 2010;125:S95–102. [PMC free article] [PubMed]
25. Mannino DM, Homa DM, Akinbami LJ, et al. Surveillance for asthma--United States, 1980–1999. MMWR Surveill Summ. 2002;51:1–13. [PubMed]
26. McFadden ER., Jr Acute severe asthma. Am J Respir Crit Care Med. 2003;168:740–759. [PubMed]
27. McKenzie SA, Chan E, Dundas I, et al. Airway resistance measured by the interrupter technique: normative data for 2–10 year olds of three ethnicities. Arch Dis Child. 2002;87:248–251. [PMC free article] [PubMed]
28. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–338. [PubMed]
29. National Heart LaBINAEaPP. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma [NIH web site] 2007 Available at: http://www.nhlbi.nih.gov/guidelines/asthma/01_front.pdf.
30. National Institutes of Health. [Accessed March 8, 2008];NIH policy on reporting race and ethnicity data: Subjects in clinical research [NIH web site web site] 2001 Aug 1; Available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html.
31. Pennock BE, Rogers RM, McCaffree DR. Changes in measured spirometric indices. What is significant? Chest. 1981;80:97–99. [PubMed]
32. Qureshi F, Pestian J, Davis P, et al. Effect of nebulized ipratropium on the hospitalization rates of children with asthma. N Engl J Med. 1998;339:1030–1035. [PubMed]
33. R Development Core Team. R: A language and environment for statistical computing [Internet web site] 2008;2008 Available at: PrFont34Bin0BinSub0Frac0Def1Margin0Margin0Jc1Indent1440Lim0Lim1 http://www.R-project.org.
34. Sanders DL, Gregg W, Aronsky D. Identifying asthma exacerbations in a pediatric emergency department: A feasibility study. Int J Med Inform. 2006 [PubMed]
35. Schenkel S. Promoting patient safety and preventing medical error in emergency departments. Acad Emerg Med. 2000;7:1204–1222. [PubMed]
36. Sherrill DL, Lebowitz MD, Knudson RJ, et al. Methodology for generating continuous prediction equations for pulmonary function measures. Comput Biomed Res. 1991;24:249–260. [PubMed]
37. Wendler D, Jenkins T. Children’s and their parents’ views on facing research risks for the benefit of others. Arch Pediatr Adolesc Med. 2008;162:9–14. [PubMed]