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Drug-related hospital admissions and responsiveness of health-related quality of life instruments in… Chow, Douglas Man Kam 2001

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D R U G - R E L A T E D H O S P I T A L A D M I S S I O N S A N D R E S P O N S I V E N E S S OF H E A L T H - R E L A T E D Q U A L I T Y OF L I F E I N S T R U M E N T S I N C H I L D R E N W I T H A S T H M A by D O U G L A S M A N K A M C H O W B.Sc.Pharm., The University of British Columbia, 1995 M . B . A . , The University of British Columbia, 1999 A THESIS S U B M I T T E D I N P A R T I A L F U L F I L L M E N T OF T H E R E Q U I R E M E N T S F O R T H E D E G R E E OF M A S T E R OF S C I E N C E in THE FACULTY OF GRADUATE STUDIES T H E F A C U L T Y OF P H A R M A C E U T I C A L S C I E N C E S We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y OF B R I T I S H C O L U M B I A June 18,2001 © Douglas M a n K a m Chow, 2 001 In presenting this thesis in partial fulfillment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representative. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. (Signature) Faculty of Pharmaceutical Sciences The University of British Columbia Vancouver, Canada Date: AV^T 21 s 7001 A B S T R A C T Objective: To evaluate (1) the frequency of drug-related hospital admissions in Canadian children with asthma and (2) the responsiveness to clinical change of the Pediatric Health Related Quality of Life Questionnaire (PAQLQ) and a "patient-specific approach" to quality of life assessment in the children. Sample: Over 12-months, 54 of 61 patients admitted to one of the study hospitals for asthma or asthma-related symptoms participated in the study. Methodology: Data were gathered by personal interviews with patients, their families, and their health-care providers; reviews of patients' health record; and administration of H R Q O L instruments. Drug-related hospital admissions were evaluated by an expert panel using a set of objective criteria to- evaluate each case. The investigator administered H R Q O L instruments to the patients during their hospital stay while they experienced acute asthma symptoms, and a second time six weeks after hospital discharge when patients were clinically improved. Results: 84% (95% CI = 73 - 95%) of 44 patients who participated in the drug-related hospital admission component of the study were deemed to have a "definite" relation between drug-intake and dose-related therapeutic failure (DTF), and 16% (95% CI = 5 -27%) had a "possible" relation between drug intake and D T F . Evidence of inadequate treatment of chronic asthma was found in 43% of cases. Evidence of inadequate treatment of acute asthma was found in 95% of cases. I f the presence of a respiratory tract infection were considered as a possible factor that could have explained patients' symptoms on hospital admission, then 52% (95% CI = 36 - 67%) of the 44 patients who participated in the drug-related hospital admission component of the study would have been deemed to have a "definite" relation between drug intake and D T F , and 48% (95% CI = 33 - 62%) would have been considered "possible" therapeutic failures. The P A Q L Q was responsive to the change in clinical status that patients experienced when they were hospitalized compared to when they were well (ES = 1.5). The P A Q L Q appeared more responsive than a patient-specific approach at assessing H R Q O L domains in pediatric patients with asthma. Conclusion: Problems related to drug therapy may be a common factor in children admitted to hospital for asthma. Most children deemed to have a drug-related hospital admission were sub-therapeutic compared with the recommendations of the National Institutes of Health (NIH) National Heart Lung and Blood Institute Expert Panel Report II Guidelines, and the Canadian Asthma Consensus Conference Summary of Recommendations. The P A Q L Q is a H R Q O L instrument that has demonstrated responsiveness to changes in patients' clinical status. "Individualized" items did not improve the responsiveness of items in a questionnaire designed to assess H R Q O L in children with asthma. T A B L E O F C O N T E N T S ABSTRACT i i LIST OF TABLES v i i LIST OF FIGURES ix LIST OF ABBREVIATIONS x LIST OF TRADE NAMES x i i DEFINITIONS x i i i ACKNOWLEDGEMENTS xiv 1. INTRODUCTION 1 2. LITERATURE REVIEW 5 2.1 D R U G - R E L A T E D H O S P I T A L A D M I S S I O N S I N P E D I A T R I C P A T I E N T S W I T H A S T H M A 5 2.1.1 Drag Use Problems: Adult Patients Wi th Asthma 5 2.1.2 Drag Use Problems: Pediatric Patients With Asthma 7 2.1.3 Drag-related Hospital Admissions 9 2.1.4 Drag-related Hospital Admissions: Adult Patients Wi th Asthma 10 2.1.5 Drag-related Hospital Admissions: Pediatric Patients With Asthma... 12 2.2 M E A S U R I N G H E A L T H - R E L A T E D Q U A L I T Y O F L I F E I N P E D I A T R I C P A T I E N T S W I T H A S T H M A 16 2.2.1 Measuring Health-related Quality of Life 16 2.2.2 Measuring Health-related Quality of Life in Adult Patients With Asthma ". 19 2.2.3 Measuring Health-related Quality of Life in Pediatric Patients With Asthma 20 2.2.4 Measurement Properties o f Pediatric Asthma-specific H R Q O L Instrument 23 2.2.5 Pediatric Asthma Quality of Life Questionnaire ( P A Q L Q ) 24 2.2.6 Using Patient Specific Items In H R Q O L Instruments to Improve Responsiveness 32 2.2.7 The Need to Evaluate Responsiveness of H R Q O L Instruments 34 i i i 3. M E T H O D S 38 3.1 E V A L U A T I O N O F D R U G - R E L A T E D H O S P I T A L - A D M I S S I O N S 38 3.1.1 Patient Recruitment 38 3.1.2 Sample Size Estimate 41 3.1.3 Data Collection 43 3.1.4 Determination of Drug-related Hospital Admission 44 3.1.5 Comparison of Patients' Drug Therapies With the Recommendations o f t h e N I H L B I Guidelines 52 3.2 E V A L U A T I O N O F H E A L T H - R E L A T E D Q U A L I T Y O F L I F E I N S T R U M E N T , 56 3.2.1 Patient Recruitment 56 3.2.2 Sample Size Considerations 56 3.2.3 Administration of Instruments 59 3.3 P R I M A R Y A N A L Y S I S 61 3.4 S E C O N D A R Y A N A L Y S I S 63 4. R E S U L T S 64 4.1 D E S C R I P T I O N O F T H E O V E R A L L S T U D Y S A M P L E 64 4.1.1 Demographic Features of Patients In the Study Sample 65 4.1.2 Clinical Features of Patients in the Overall Study Sample 69 4.1.3 Drug-related Hospital Admission Cohort 73 4.1.4 Patients Diagnosed With Asthma for the First Time During The Hospital Admission 74 4.1.5 Health-related Quality o f Life Assessment Cohort 75 4.2 T H E C H R O N I C A N D A C U T E D R U G R E G I M E N O F T H E P A T I E N T S I N T H E D R U G - R E L A T E D H O S P I T A L A D M I S S I O N C O H O R T 75 4.2.1 Medications Taken For the Chronic Management of Asthma 76 4.2.2 Medications Taken For the Acute Exacerbation 80 4.3 E V A L U A T I O N O F D R U G - R E L A T E D H O S P I T A L A D M I S S I O N S 87 4.3.1 Effects o f Symptoms of U R T I on Drug-related Admissions 87 4.3.2 Patients' Drug Therapy In Relation to the Recommendations of the N H L B I Guidelines 92 iv 4.4 H E A L T H - R E L A T E D Q U A L I T Y O F L I F E 106 4.4.1 Description of the Study Sample 106 4.4.2 H R Q O L Scores Measured During the Hospital Stay 107 4.4.3 Change in H R Q O L Scores Measured Six Weeks After Hospital Stay 117 5 ' DISCUSSION 126 5.1 T H E O V E R A L L S T U D Y S A M P L E 126 5.2 D R U G - R E L A T E D H O S P I T A L A D M I S S I O N S 130 5.2.1 Drug Regimen of Patients in the Drug-related Hospital Admission Cohort 132 5.2.2 Modification of Hal las 'Algor i thm 134 5.2.3 Interpretation of Hallas' Algorithm In Relation to Respiratory Tract Infections 136 5.2.4 Lack of Inhaled and Oral Corticosteroids Reported in the Regimen.. 141 5.2.5 Lack of Adherence to Evidence-based Guidelines 145 5.2.6 Under-diagnosis of Asthma 151 5.2.7 Prevention 151 5.3 H E A L T H - R E L A T E D Q U A L I T Y O F L I F E 156 5.3.1 The Study Sample 156 5.3.2 H R Q O L Measured During Hospital Stay 157 5.3.3 Change In H R Q O L Six Weeks After Hospital Stay 162 6 C O N C L U S I O N 168 7. R E F E R E N C E S . 170 APPENDIX 1 180 APPENDIX 2 193 APPENDIX 3 208 APPENDIX 4 216 APPENDIX 5 225 v APPENDIX 6 240 APPENDIX 7 245 APPENDIX 8 253 APPENDIX 9 259 APPENDIX 10 261 APPENDIX 11 263 APPENDIX 12 265 APPENDIX 13 266 APPENDIX 14 270 APPENDIX 15 273 APPENDIX 16 276 APPENDIX 17 279 APPENDIX 18 281 APPENDIX 19 283 v i L I S T O F T A B L E S Table 1 Asthma-Specific Instruments Designed to Measure the Effect of Asthma on Pediatric Patients 22 Table 2 Age-specific Questionnaires 25 Table 3 The Subscales of the C A Q 26 Table 4 Methods of Classifying Change In Patients 30 Table 5 Pearson Correlation Coefficients Showing Cross Sectional Construct Validity 31 Table 6 Inclusion Criteria 40 Table 7 Sample Size Estimates For 95% Confidence Interval 42 Table 8 Criteria Used to Characterize the Relation Between Drug Intake and A D R 45 Table 9 Criteria Used to Characterize the Relation Between Drug Intake and T F 46 Table 10 Significance For Hospital Admission 47 Table 12 Classification of Avoidable Admissions 56 Table 13 Number of Pairded Observations Required 58 Table 14 Quality of Life Instrument Administered B y Age Group 62 Table 15 Age, Height, A n d Weight O f Patients In The Overall Study Sample.. 68 Table 16 Mean Values of Heart Rate and P E F R on Admission of the 70 Table 17 Expected Heart Rates For Infants and Children 71 Table 18 Evidence From Patients' Case Summaries of a Condition That Could Have Explained the Symptoms In the Seven Cases Deemed to Be "Possibly" Drug-related B y the Panel 89 Table 19 Fourteen Additional Cases of Patients With Evidence of a Respiratory Tract Infection Identified by the Investigator 91 Table 20 Presence of Inadequate Chronic Treatment of Patients with " M i l d -Persistent" Asthma 94 Table 21 Presence o f Inadequate Chronic Treatment with Chronic Drug Therapy in Patients with "Moderate-Persistent" Asthma 97 Table 22 Presence of Inadequate Acute Treatment of Patients with " M i l d -Intermittent" Asthma 100 Table 23 Presence of Inadequate Acute Treatment of Patients with " M i l d -Persistent" Chronic Severity 102 v i i Table 24 Presence o f Inadequate Acute Treatment of Patients with "Moderate-Persistent" Chronic Severity 104 Table 25 Presence of Inadequate Acute Treatment of Patients with "Non-Determinable" Chronic Severity 105 Table 26 C A Q - A Scores Measured During The Hospital Stay 108 Table 27 C A Q - B Scores Measured During The Hospital Stay 110 Table 28 C A Q - C Scores Measured During The Hospital Stay I l l Table 29 P A Q L Q Scores Measured During the Hospital Stay 113 Table 30 Parents' P A C Q L Q Scores Measured During the Hospital Stay 114 Table 31 Parents' Q O L i F Scores Administered During the Hospital Stay 115 Table 32 Children's Q O L i F Scores Measured During the Hospital Stay 116 Table 33 Children's P A Q L Q Scores Measured During Hospital Admission and Six Weeks After Hospital Stay 119 Table 34 P A C Q L Q Scores Measured 6 Weeks After the Hospital Stay 120 Table 35 Parents' Q O L i F Scores Measured During Hospital Admission and 6 Weeks After Hospital Stay 123 Table 36 Children's Q O L i F Scores For the Physical, Role and Social Domain Measured During Hospital Stay and 6 Weeks After Hospital Stay.... 124 Table 37 Comparison of Scores in the Physical Domain o f the Q O L i F and Activity Domain Scores of the P A Q L Q in the Group of Six Children Who Completed Both the P A Q L Q and the Q O L i F 125 v i i i L I S T O F F I G U R E S Figure 1 Number of Children Enrolled Per Month (n=54) 66 Figure 2 Age Distribution of Patients in the Study Sample (n=54) 67 Figure 3 Normal Respiratory Rates In Children 72 Figure 4 Distribution of Prescription Medications Prescribed For the Chronic Management of Asthma A s Reported B y Patients or Parent(s) of Patients 77 Figure 5 Types of Medication Prescribed For the Chronic Management of Asthma A s Reported B y Patients or Parent(s) of the Patients 78 Figure 6 Distribution of Regularly-Scheduled Medications Prescribed For the Chronic Management of Asthma as Reported by the Patient or the Parent(s) of the Patient 79 Figure 7 Types of Regularly-Scheduled Medications Reported by the Patient or the Parent(s) of the Patient to be in the Patient's Regimen for the Chronic Management of Asthma 81 Figure 8 Distribution of "As-needed" Medications Reported by the Patient or Parent(s) of the Patient to be in the Patient's Regimen for the Chronic Management of Asthma 82 Figure 9 Types of "As-needed" Medications Reported by the Patient or the Parent(s) of the Patient to be in the Patient's Regimen for the Chronic Management of Asthma 83 Figure 10 Distribution of Number of Medications that Patients Reported Taking for the Acute Episode 85 Figure 11 Types of Medications that the Patients Reported Taking for the Acute Episode 86 Figure 12 Classification of D R H A s 88 ix L I S T O F A B B R E V I A T I O N S A D R adverse drug reaction B C C H British Columbia's Children's Hospital B P blood pressure C O P D chronic obstructive pulmonary disease D R H A drug-related hospital admission D R P drug-related problem D T F dose-related therapeutic failure G P general practitioner H R heart rate H R Q O L health-related quality of life I C C intra-class correlation coefficient M C I D minimal clinically important difference4 M D I metered-dose inhaler M S J Mount Saint Joseph Hospital N A not available N D not determinable N H L B I National Heart, Lung and Blood Institute N I H National Institutes of Health P R N as needed; taking medication liberally P R N * regularly as-needed; taking medication as needed and taking it regularly. A n example is taking medication three times a day for two weeks upon start of upper respiratory tract infection. Q O L quality of life R R respiratory rate SD standard deviation T F therapeutic failure U R T I upper respiratory tract infection W H O World Health Organization x i L I S T O F T R A D E N A M E S Listings by brand name are in the following format: Brand Name (Manufacturer) generic name Advil (Whitehall-Robins) ibuprofen Alupent (Boehringer Ingelheim) orciprenaline sulfate Atrovent Inhalation Aerosol (Boehinger In gelheim) ipratropium bromide Becloforte (Glaxo Wellcome) betamethasone dipropionate Benylin-DM-D For Children (Warner-Lambert Consumer Healthcare) dextromethorphan hydrobromide/pseudoephedrine hydrocholoride Bricanyl Turbuhaler (Astra) terbutaline sulphate Dimetapp (Whitehall-Robins) brompheniramine maleate, phenylephrine hydrochloride phenylpropanolamine hydrocholoride Intal (Rhone-Poulenc Rorer) sodium cromoglycate Pulmicort Turbuhaler (Astra) budesonide Ventolin Inhalation Aerosol (Glaxo Wellcome) salbutamol sulfate Ventolin Nebules P.F/Respirator Solution (Glaxo Wellcome) salbutamol sulfate Tilade (Fisons) nedocromil sodium Tylenol (McNeil Consumer Products) acetaminophen xii D E F I N I T I O N S adverse drug reaction therapeutic failure quality o f life health-related quality of life adverse drug reaction; a toxic reaction or a noxious, unintended drug reaction that occurs at doses normally used in man for prophylaxis, diagnosis, or therapy2 an absence of therapeutic response that could be linked causally either to a prescribed dose that was too low, to drug compliance, recent dose reduction/discontinuation, interaction or inadequate monitoring. 2 A person's sense of well-being that stems from satisfaction or dissatisfaction with the areas of life that are important to him/her. 3 the functional effect of an illness and its consequent therapy upon a patient, as perceived by the patient4; those parts of Q O L that are affected by health only. x i i i A C K N O W L E D G E M E N T S Bruce Carleton, Pharm.D. Marc Levine, Ph.D. Susan Heathcote, B . S . N , R . N . , Utilization Reviewer Timothy John-Grainger Rousseau, Ph.D. Lee Boshell, B . S . N . , R . N . , D . A . C . Alexander Ferguson, M . D . , F R C P C John Dean, M . D . , F R C P C Michael Seear, M . D . , F R C P C David Wensley, M . D . , F R C P C Dennis Primmett, Ph.D. Carlo Marra, Pharm.D. Diane Vi l lany i , B.Sc.(Pharm) First and foremost I would like to thank Dr. Marc Levine and Dr . Bruce Carleton, my supervisors, for their direct support, time, and dedication to this project. With their guidance and their efforts, they have provided a tremendous amount of insight and experience to make this research possible. I would also like to thank Susan Heathcote from Children's and Women's Health Centre of British Columbia and Lee Boshell from the Pharmaceutical Outcomes Research Program for their work at the hospital. I also owe much gratitude and much clinical support from Dr. Alexander Ferguson, Dr. John Dean, Dr. Wensley, and Dr. Michael Seear who opened up their clinics for me to be exposed to their daily practice in managing children with asthma. Thank you Dr. Primmett, Dr . Carlo Marro, and Diane Vi l l any i for your input, suggestions and support during this project. Finally I would like to thank my girlfriend, L i z and my parents for their love. x i v 1. I N T R O D U C T I O N Asthma is the most common chronic medical condition in children in Canada and the United States. 5 " 7 Patients with asthma suffer from a chronic inflammatory disorder of the lungs, which is characterized by inflammation, epithelial damage, bronchiole constriction, obstruction, and hyper-reactivity to environmental stimuli. 8 These patients are more symptomatic when exposed to factors that can trigger their asthma, including respiratory tract infections, ozone, and other environmental irritants. Triggers can often cause patients to exhibit wheezing, shortness of breath, chest tightness, and coughing. Symptoms can be severe enough for patients to be admitted to hospital and some patients with severe exacerbations who are not treated properly can die. Asthma accounts for approximately 500,000 hospitalizations annually in the United States and approximately 198,000 hospitalizations in the population less than 25 years of age. 1 3 Furthermore, the incidence of asthma-related mortality and morbidity has 9 13 been increasing, especially in the North American pediatric population. In the U S A , asthma-related hospitalizations rates have increased by approximately 4.5% per year among children less than 17 years of age over the last decade. 1 4 The frequency of asthma related morbidity has also increased among Canadian children. 1 5 2 2 These trends are occurring despite the development of efficacious medications, 2 3 which reduce the clinical features of an asthma exacerbation by decreasing airway 1 constriction and inflammation. For example, it has been reported that corticosteroids suppress inflammation in asthmatic airways, improve lung function, reduce symptoms, prevent exacerbations, and reduce the incidence of hospital admissions, 2 5" 2 9 reduce asthma mortality, 3 0 reduce the irreversible changes in airway function, and improve 31 patients' health-related quality of life. Furthermore, asthma treatment guidelines, including the National Institutes of Health (NIH) National Heart Lung and Blood 32 Institute Expert Panel Report II Guidelines and the Canadian Asthma Consensus Conference Summary of Recommendations,33 have been developed to help patients, physicians, and other members of the healthcare team manage the disease with these drugs. The content of the National Institutes of Health (NIH) National Heart Lung and Blood Institute Expert Panel Report II Guidelines reflect the current state of knowledge about the pathophysiology of the disease. Its recommendations to guide the management of asthma have been based on evidence from the scientific literature, the expert judgement and collective opinion of the members of the expert panel, and approval of the Coordinating Committee of the National Asthma Education Program. The Canadian Guidelines have also been based on the evidence from the scientific literature and the input from a panel of specialists and general practitioners in medicine. However, the number of children admitted to hospital for asthma is growing despite the publication of the guidelines and the availability of efficacious medications. One explanation for the increased frequency of asthma-related hospital admissions in children, despite the availability of efficacious medication in 2 North America is inadequate treatment. Children's drug regimens may be inconsistent with the recommendations of the published asthma treatment guidelines. Poor management of children's asthma may be contributing to the high incidence of hospital admission of children with asthma in North America. However, the frequency of drug-related hospital admissions in pediatric patients with asthma is not known. Asthma can also interfere with physical and social activities, disrupt growth and development in children, and consequently have a large impact on children's health related quality of life ( H R Q O L ) . Thus asthma-related H R Q O L has been recognized as an important endpoint to measure in clinical trials. Current state of the art instruments, the P A Q L Q and the C A Q have been shown to be valid and reliable. However, for these instruments to be useful in longitudinal trials, these instruments must also be responsive to change over time. However, the responsiveness to clinical change of these instruments has not yet been evaluated. The following thesis serves to estimate the frequency of drug-related hospital admissions in children with asthma. The second objective of this thesis was to examine the responsiveness o f two health-related quality of life instruments. A final objective was to conduct initial hypothesis testing of an individualized approach to pediatric H R Q O L assessment. The next section of this thesis reviews what is currently known about 3 drug-related hospital admissions in the pediatric patient population with asthma and the current status of health-related quality of life instruments designed to measure health-related quality of life in pediatric patients with asthma. 4 2. L I T E R A T U R E R E V I E W The following section reviews the existing research in the area of drug-related hospital admissions in the pediatric patient population with asthma (Section 2.1) and the health-related quality of life instruments for pediatric patients with asthma (Section 2.2). 2.1 D R U G - R E L A T E D H O S P I T A L ADMISSIONS IN P E D I A T R I C P A T I E N T S W I T H A S T H M A The role drugs play in the causation of hospitalization in children with asthma has not been well studied. More research has been done examining morbidity associated with drug use in patients with asthma, so a description of this literature is appropriate. The linkage between drug use and hospital admission may be stronger in patients with asthma, since they are generally taking multiple medications over long periods of time. Sections 2.1.1 and 2.1.2 provide a description of the epidemiology of problems associated with drug use in adult and pediatric patients with asthma. A description of the epidemiology o f drug-related hospital admissions in adults and pediatric patients with asthma follows (Section 2.1.3). 2.1.1 D R U G USE P R O B L E M S : A D U L T PATIENTS W I T H A S T H M A Problems related to drug therapy are common in patients with asthma. A study of asthma mortality rates found that 61% of asthmatic patients had insufficient medication to control their disease and 54% showed poor compliance before their deaths.3 4"3 5 5 Nonadherence to asthma medication ranged from 30% to 70%. Hartert et al. examined the adequacy of chronic medication use in adult patients who lived in urban areas with moderate or severe asthma. The investigators examined physician adherence to the guidelines for asthma management published by the National Asthma Education and Prevention Program ( N A E P ) . Only 28% of the patients had been given an action plan by their physicians in the event of an acute exacerbation. Sixty percent of patients who contacted their physicians during the exacerbation that preceded admission had no changes made to their regimen. Only 11% were able to demonstrate proper use of their inhaler. no Tettersell et al. investigated patients' knowledge of asthma and compliance with asthma medications using a postal survey among a group of 100 patients with moderate to severe asthma. They reported that 39% of patients in their study did not take their medication as directed and 48% of these patients were non-compliant because they believed their medications were unnecessary or were embarrassed about taking their inhaler medication in public. Furthermore, 76% of patients who reported to be non-compliant claimed that they did not take their prescribed preventative medications. Inappropriate use of preventative medications has also been reported by Laumann et al.39 in a larger study of 1,029 adult patients with asthma. Using a disease-based drug utilization review methodology, the investigators compared patients actual drug therapies to the latest international asthma treatment guidelines. About half of patients who should 6 have been prescribed inhaled steroids based on disease severity did not have such a prescription filled. 2.1.2 D R U G USE P R O B L E M S : PEDIATRIC PATIENTS W I T H A S T H M A Children with asthma may be even more prone to drug use problems than adults because younger patients are less likely to comply to asthma drug therapy. 3 8 Children may also be prone to drug use problems because objective measures of airways obstruction may be more difficult to assess reliably in children than in adults. 4 0 These measures may also be less reliable in children since many breathing tests are effort dependent and require full cooperation and concentration o f the subject performing the test. Furthermore, children are generally less capable of accurately describing their symptoms to clinicians than adults. Thus, clinicians' evaluations of children's subjective perception of disease severity may be less reliable than in adults. However, even among adults, symptoms of asthma such as wheezing, breath sound intensity, forced expiratory time, accessory muscle use, respiratory rate and pulsus paradoxus are known to correlate poorly with airway obstruction in one-third to one-half of asthmatic patients.4 1 Clinicians disagree about the presence or absence o f respiratory signs 55% to 89% of the time, correctly predict pulmonary function based on history and physical examination only about half the time, and correctly diagnose asthma based on the clinical examination only 63% to 74% of the t ime. 4 1 Moreover, many children resent having to take medication chronically for asthma. Children have reported that they would discontinue treatment i f they felt w e l l 4 2 For all these reasons children with asthma may be prone to develop adverse drug 7 reactions or dose-related therapeutic failures that may lead to hospitalization. Milgrom. et al.43 evaluated the adherence of children with asthma to regimens of inhaled corticosteroids and beta-agonists. Data collected electronically by metered-dose inhaler chronolog monitors (devices that record when patients actually use their medications), were compared with data recorded by patients on traditional diary cards. More than 90% of patients exaggerated their use of inhaled steroids and diary entries. Electronic monitoring demonstrated much lower adherence to prescribed therapy than was reported by patients on diary cards. L o w rates of compliance with prescribed inhaled corticosteroids were associated with exacerbation of disease. The median compliance with inhaled corticosteroids was 13.7% for those who experienced exacerbations and 68.2 % for those who did not. In a more recent study, Bender et al. reported that children with asthma seldom take all o f their medications as prescribed 4 4 In their study that utilized electronic monitoring, they found patients failed to take any inhaled corticosteroid doses on 41.8% of days or inhaled pVagonists on 28.1% of days despite prescribed daily use. Thus, the extent o f non-compliance in the pediatric patient population may be worse than previous estimates suggest. 8 2.1.3 D R U G - R E L A T E D H O S P I T A L A D M I S S I O N S Drug-related hospital admissions are hospital admissions caused by adverse drug reactions or therapeutic failure of drugs. The reported rates of drug-related hospital admissions, excluding intentional overdoses, alcohol intoxication, and il l ici t drug use, range from 0.2 - 22 .3%. 4 5 - 4 6 Einarson et al?5 performed a meta-analysis of studies that evaluated this frequency of drug-related hospital admissions. They estimated that 0.2 % to 21.7 %, with a median of 4.9% of hospital admissions are caused by problems related to drug therapy. The differences in reported rates of drug-related hospital admissions may have been caused by differences in prescribing practices, scope of population sampling, the intensity of data collection, methods of evaluating adverse drug reactions and therapeutic failures, and variations in the definitions used to classify adverse drug reactions and therapeutic failures. Methods of evaluating problems with drugs contributing to hospital admissions have evolved in the last several decades since the first investigations about drug-related hospital admissions were reported in the literature. Before the mid 1970s, studies performed to estimate the frequency of drug-related hospital admissions relied more on subjective opinions o f clinical investigators. 4 7 Without a set of operational criteria to establish the presence o f a drug-related hospital admission, the conclusions drawn from these earlier studies have been difficult to interpret and generalize. Since then researchers have begun to use more operationally defined criteria to establish 9 the presence of drug-related hospital admissions. A number of algorithms have been developed, and the most significant work has been done by Karch et al.,41 Naranjo et a/., 4 8 Bergman et al.,49 Larmour et al.50 and Hallas et al.2 One of the more commonly used methods reported in the current literature is Hallas' a lgori thm. 2 ' 5 1 " 5 4 ^Hallas et al.2 developed the algorithm for evaluating drug-related hospital admissions using methods originally published by Karch et al. . 5 5 Hallas et al? classify drug-related problems as "adverse drug reactions" or "dose-related therapeutic failures." According to their criteria, an adverse drug reaction is any unintended and undesirable effect of a drug. A dose-related therapeutic failure is a lack of therapeutic effect that could be ascribed to non-compliance, inappropriate administration technique, recent dose reduction/discontinuation, interaction, inadequate dose prescribed, or inadequate monitoring. Non-prescription o f a drug, or non-compliance unaccompanied by clinical symptoms are not considered dose-related therapeutic failures. Some validity testing of the algorithm has been done. 5 2 2.1.3.1 D R U G - R E L A T E D H O S P I T A L ADMISSIONS: A D U L T PATIENTS W I T H A S T H M A Some conclusions can be inferred about drug-related hospital admissions in the pediatric patient population from studies in the adult population. However, very little work has been done, even in the adult population. 10 Hallas' work in 1992 suggested that the frequency o f drug-related hospital admissions may be high in the population of patients with asthma. In fact, non-compliance with prescribed anti-asthmatic medication was a cause of dose-related therapeutic failure in six of the 16 cases reported in the study. Previous studies that have examined drug-related hospital admissions in the general adult population have not included illness caused by underprescribing or inappropriate choice of medication. In fact, Einarson's 3 5 study did not include underprescribing or inappropriate choice of medication. The reason these researchers did not include these important determinants to drug-related hospital admissions was that with the multitude of conditions that patients may admitted to hospital for, it would have been difficult to debate which drugs should have been required for each case. Thus, the frequency o f drug-related hospital admissions as a cause of asthma-related hospital admission has not been well quantified in the adult population. In the case o f the patients with asthma, however, explicit treatment guidelines that clearly indicate which medications are recommended have been published. Thus, it would be possible to quantify using Hallas' algorithm, the frequency of drugs being a contributing factor to hospital admission in patients with asthma. However, to date, no such studies have been published, even in the adult population. 11 2.1.3.2 D R U G - R E L A T E D H O S P I T A L ADMISSIONS: P E D I A T R I C PATIENTS W I T H A S T H M A Even less is known about the role of drugs as a cause of hospital admissions in pediatric patients with asthma. However, some studies suggest that it may be a widespread and important problem that needs to be investigated. For example, Lozano et al.56 have estimated that children with asthma incur twice as many inpatient days (0.23 vs. 0.11/yr) compared to the general population of children and that hospital care for children with asthma accounts for approximately 33% of the total cost of asthma care. A small group of patients with asthma may be heavy users of the acute health-care system. Furthermore, a subgroup of patients appear to have a very high frequency of hospitalizations. Hospital readmission rates among children with asthma has been estimated to be approximately 43 15 57 to 47%. ' If it were true that children admitted to hospital are caused by problems related to drug therapy, then by targeting preventative measures at the select group of patients who are most frequently hospitalized, substantial healthcare dollars may be saved. To achieve this goal, however, it is necessary to understand the true rates of drug-related hospital admissions and to understand the reason why so many children are hospitalized each year for asthma. A number of reasons for the high frequency of hospitalization in children with asthma have been identified. These include exposure to environmental pollutants, poverty, and drug-related problems. Little can be done about some o f these factors. For example, poverty is a social-economic issue. Inappropriate medication use, 12 however, is a factor that clinicians may be able to address. Thus, it is imperative that a better understanding be gained of the role of drugs in causing hospitalization. More recently, the discovery that inflammation plays a substantial role in the pathogenesis of asthma has sparked renewed interest in the role o f drugs as causative factors of hospitalization in patients with asthma. The incidence of drug-related hospital admissions in the pediatric patient population with asthma may be higher than previously suspected. In 1992, Macarthur et al.15 found that factors related to children's risk of hospital readmission included care by a specialist and prophylactic use of inhaled corticosteroids. Children not prescribed prophylactic steroids were more likely to be readmitted to hospital than children who were prescribed prophylactic steroids. Furthermore, children who were under the care of a specialist were less likely to be admitted than children who were only under the care of a family physician. Surprisingly, asthma severity was not associated with hospital readmissions. These conclusions support the hypothesis that efficacious drug therapies may not be optimized and are thus less effective than they could be in asthma-related hospitalizations in children. C D Yosselson-Superstine et al. have examined the role o f drug-related hospitalizations in pediatric patients. Approximately 18% of the 906 studied admissions in Jerusalem, Israel were found to be drug-related. Eleven percent was as result of inappropriate drug therapy, 3.4 % as a result o f patient non-compliance, and 3.2% as a result of adverse reactions. However, their study population included all pediatric 13 patients admitted to hospital and their results may not apply to the subgroup of asthmatic pediatric patients. Prior to this study, only two published studies in the Medline™ database examined the association between drugs and hospitalization in pediatric patients with asthma' Abduelrhman et al.59 examined the adequacy of pre-hospital treatment in pediatric asthmatic patients in Galway, Ireland in 1990. In this prospective study, 105 children between one and 14 years of age who were admitted to hospital for asthma were studied. They reported that "absence o f regular prophylaxis despite adequate indication, poor compliance with prescribed regimens, and inappropriate management o f the acute attacks" 5 9 were common characteristics in pediatric asthmatic patients hospitalized. Overall, 10% of patients lacked adequate prophylaxis and 5% of patients were non-compliant with medications. Several methodological problems o f the study, however, make their results difficult to generalize to pediatric patients in Canada. First, the population that they studied consisted of children aged one to 14. However, the definition of asthma is poorly defined in children less than five years of age. Second, the pre-hospital treatments of pediatric patients with asthma i n this study were evaluated by a single evaluator. It is not known how reliable this evaluator was or whether the conclusions of this evaluator agree with others. Third, whether or not the evaluator was qualified to make the assessments was not reported. Fourth, the method used to evaluate "inadequate pretreatments," a 14 type of drug-related problem, was not reported. Abduelrhman et al. did not use a formal algorithm to evaluate the how the drugs may have contributed to hospital admissions. Koch-Weser et al.60 have shown that without a standardized algorithm for evaluating a relation between a drug and an adverse event, such as hospitalization, results are highly variable. For example in their study, they examined only one type of problem, adverse drug reactions, and found that disagreements about reported A D R s among evaluators were as high as 56.8%. 6 0 Fifth, in the study by Abduelrhman et al., the standards of practice from which the therapies were judged inadequate were not described. Finally, in Galway, access to health care, medication available, and patient education are different from Canada's and the U S A ' s . These factors affect the risk of having drug-related hospital admissions. Thus, although the study by Abduelrhman et al. suggests that drug-related hospital admissions may exist in Canada, a good estimate of the extent of the problem in the Canadian population is not available. The second study was done in 1979. Sublett et al.61 found that 98% o f 50 children who arrived to the emergency room with an acute asthmatic attack had subtherapeutic theophylline blood levels and 75.5% of the patients admitted that they had not complied with their physicians' instructions. However, the major weakness with this study is that this study occurred over 20 years ago when the modern clinical guidelines for corticosteroid therapy had not yet been established. Considering the scientific evidence of the effectiveness o f corticosteroids in reducing the symptoms o f acute asthma exacerbations and the effectiveness o f these agents at preventing exacerbations, the 15 frequency of drug-related hospital admissions in the pediatric patient population admitted to hospital may be very high indeed. The following study fills the gap in knowledge about the frequency of drug-related hospital admissions in pediatric patients with asthma. B y using a modification of Hallas ' 'algorithm to estimate the frequency of drug-related hospital admissions, this study focuses primarily on those types o f drug-related hospital admissions caused by therapeutic failures rather than adverse drug reactions and includes those types of therapeutic failures that may be related to under-prescribing or inappropriate choice of medication. 2.2 M E A S U R I N G H E A L T H - R E L A T E D Q U A L I T Y O F L I F E IN P E D I A T R I C P A T I E N T S W I T H A S T H M A 2.2.1 M E A S U R I N G H E A L T H R E L A T E D Q U A L I T Y O F L I F E Health related quality o f life is loosely defined as the effect o f a person's health status on an individual's quality of life. A s such an abstract concept, there has been a lack of a consensus in the current literature about the definition of H R Q O L and how it should best be measured. The recent literature suggests that H R Q O L is a multi-dimensional concept consisting of several "domains." Although the exact number of domains may vary among various definitions, the domains most commonly reported include physical, psychological, social, role functioning, and general health perception. Thus, the current 16 literature defines health related quality of life as the impact of health on a person's physical, psychological, social and role functioning, and general health perception. Ware et al. have provided a useful analogy to understand H R Q O L . The impact of a disease or health is like a rock hitting the surface of a pond, sending ripples over the entire surface. L ike the ripples spreading out, disease first affects the biological function of a person and then creates specific symptoms and problems. These in turn affect a person's physical and mental health, social well-being, and role functioning. The total effect, including the impact on the patients' physical and mental health is the complete effect of the disease on the patient. If clinicians or researchers were to measure the impact of a disease by simply assessing its effects on a patient's biological functioning, then they would not be capturing the whole effect of the impact of the disease. Health related quality o f life is a more comprehensive concept that captures the entire effect of a disease on a patient. Thus, H R Q O L is an important endpoint that needs to be evaluated. 6 3 When used with other endpoints, evaluation of H R Q O L can help to better understand the full impact of disease on a patient. Furthermore, many chronic diseases today can only be treated but not cured. Therefore, measures o f traditional outcomes like mortality rates would not be able to fully capture the full effect of treatments in populations. In addition, many biological markers that have been used as surrogate markers o f patients' quality of life may be poorly correlated with how patients actually feel or perform in their daily 17 activities. Without measuring the H R Q O L directly, other measures may not be fully assessing the impact of a medical intervention on patients' lives. Knowing the full effect of medical interventions on patients' lives can help decision makers direct resources to those medical interventions that provide the most benefit to patients. ' A large number of instruments have been developed to assess H R Q O L . Some of these include the Sickness Impact Profile (SIP), the Nottingham Health Profile (NIH), and the McMaster Health Questionnaire, which comes in several forms (SF-36, SF-20, SF-12). These generic instruments have been found to be useful in many, but not all patient groups. They have been found to be particularly useful in those patients with multiple disease states, severe disease, the elderly, and the handicapped. However, for some specific sub-populations of patients these generic instruments may contain irrelevant questions, which may reduce the sensitivity of the instruments to detect clinical changes. Disease-specific instruments have been developed to improve the applicability of the H R Q O L questionnaires to patients with certain medical conditions. In general, these instruments have been found to be more responsive to clinical change and more useful for monitoring patients over time than the generic instruments. They have also been less of a burden to administer to patients with specific disease. Disease specific instruments have been developed for patients with cancers, 6 4 rheumatoid arthritis, and asthma. 6 5 18 2.2.2 M E A S U R I N G H E A L T H - R E L A T E D Q U A L I T Y O F L I F E IN ADULT PATIENTS W I T H A S T H M A Asthma is a chronic disease where the assessment of H R Q O L is especially useful. 6 5" 6 8 Jones et al.69 have shown that objective clinical measurements correlate poorly with disease severity in patients that suffer from asthma. For example, P E F and F E V i are known to correlate poorly with symptom severity or with the effect of the disease on the social and psychological well-being o f patients. Furthermore, physicians appear to estimate their patients' health using criteria different from the patients themselves. 7 1 Thus, H R Q O L instruments can provide a more direct assessment o f the impact o f asthma on patients. Furthermore, the objectives of modern asthma treatment are not only to maintain "normal" pulmonary function, but also to live a life free of restrictions from everyday activities. H R Q O L questionnaires can directly assess this outcome. B y using H R Q O L assessments, clinicians can identify a threshold response to treatment that may be considered "worthwhile", and researchers can obtain a more complete comparison o f the effectiveness o f therapies. Some of the more commonly reported instruments in the literature for the assessment of H R Q O L in the adult population with asthma include the Asthma Quality of Life Questionnaire ( A Q L Q ) , L iv ing With Asthma Questionnaire ( L W A ) , Asthma Symptom Util i ty Index (ASUI) , the Sydney Asthma quality of Life Questionnaire 19 (Sydney A Q L Q ) , and others. These asthma-specific H R Q O L instruments are usually in the form of a series o f scales that patients use to rate the effect of asthma on aspects of their lives that are affected by asthma. Patients' scores on these scales are then used to calculate a numerical value to represent the patients' H R Q O L status. 2.2.3 M E A S U R I N G H E A L T H - R E L A T E D Q U A L I T Y O F L I F E IN PEDIATRIC PATIENTS W I T H A S T H M A It is just as important to evaluate H R Q O L in children with asthma as it is in adults with 72 asthma. The H R Q O L instruments designed for the adult population, however, are not useful in children. Furthermore, parents' perception of their children's H R Q O L may not be accurate. 7 3 Children require H R Q O L instruments designed for their level of comprehension. 7 4" 7 5 A review o f the Medline™ database from 1966-1998 has revealed that ten instruments have been designed to assess children's or their parents' perceptions about asthma on their l i v e s . 7 6 ' 7 7 The names of these instruments and the type o f respondent the instruments have been designed for are listed in Table 1. Six of these instruments have been designed for parents as respondents. Only four of the ten have been designed for children as respondents. O f the four instruments that have been designed for children to respond to, only two evaluate H R Q O L as a multi-dimensional concept. They are the 20 Childhood Asthma Questionnaire ( C A Q ) and the Pediatric Asthma Quality of Life Questionnaire ( P A Q L Q ) . 21 Table 1 Asthma-Specific Instruments Designed to Measure the Effect of Asthma on Pediatric Patients Instrument Respondent Parents Children Asthma Symptom A n d Disability Questionnaire X Chi ld Health Survey " X Functional Status II (R) X Quality of Life Factors X Functional Severity of Asthma Scale X Childhood Attitudes Towards Illness Scale (CATIS) X X (8-12 years) Life Activities Questionnaire For Childhood Asthma X X (5-17 years) Pediatric Asthma Quality of Life Questionnaire X X (7-17 years) Childhood Asthma Questionnaire X X (4-16 years) About M y Asthma 7 7 X ( £ 5 * grade) 22 2.2.4 M E A S U R E M E N T PROPERTIES O F PEDIATRIC A S T H M A - S P E C I F I C H R Q O L INSTRUMENTS Like other tools in the social and behavioural sciences designed to measure abstract concepts, psychometric properties o f the instruments are important determinants o f the utility of H R Q O L instruments. The most important psychometric properties of H R Q O L instruments are validity, reliability, and responsiveness. In general, validity refers to the extent that an instrument measures what it is intended to measure. 7 8 Reliability refers to the extent that an instrument measures the same result on repeated trials. 7 8 Responsiveness refers to the extent that a measurement is able to detect clinically meaningful change. So far, very little has been done to evaluate the responsiveness of these instruments to clinical change. Responsiveness is a property that can help researchers and clinicians interpret clinically important change in H R Q O L measures. 2.2.4.1 C H I L D H O O D A S T H M A Q U E S T I O N N A I R E (CAQ) The Childhood Asthma Questionnaire ( C A Q ) is a child-centred instrument that examines children's own perception about how asthma affects their H R Q O L . The self-administered C A Q has been designed to obtain responses directly from children and to minimize parental influence. Ease of use, children's interests, and children's level of comprehension are factors that have been taken into account in the design of the 23 instrument. The development of the C A Q has been reported. / y The C A Q is comprised of three different age-specific questionnaires, the C A Q - A , C A Q - B , and the C A Q - C as shown in Table 2 and Appendices 1 to 3. The three age-specific questionnaires address the wide range of comprehension levels and lifestyles of pre-school children to teenagers. Each of the three age-specific questionnaires is comprised o f different domains, which have been derived by factor analysis. The domains of each o f these instruments are summarized i n Table 3. Only the responsiveness of the C A Q - C has been investigated. N o studies have yet evaluated the responsiveness of the C A Q - A or the C A Q - B . 2.2.5 PEDIATRIC A S T H M A Q U A L I T Y O F L I F E QUESTIONNAIRE (PAQLQ) The P A Q L Q 8 0 (shown in Appendix 4) was designed to evaluate H R Q O L in pediatric patients with asthma aged seven to 17. It has shown to be reliable in the age groups for which it was designed. 8 1 The P A Q L Q can be self-administered or interviewer-administered. In addition, it has an optional component designed to assess the impact of asthma on the caregiver ( P A C Q L Q ) . A unique feature of the P A Q L Q is a set of "individualized" questions that assess the impact of asthma on a child's ability to perform physical activities. These individualized questions are supposed to 24 Table 2 Age-specific Questionnaires The CAQ is comprised of three age-specific formats. The age specific age group of each instrument, and the unique features of each instrument are described in each column. Instrument Age Unique Features C A Q - A 4-7 • Requires assistance of adult • Children colour-in the questionnaire C A Q - B 8-11 • Self-administered • Children colour-in the boxes C A Q - C 12+ • Self-administered • Children insert numbers adjacent to items 25 Table 3 The Subscales of the Childhood Asthma Questionnaire C A Q - A C A Q - B C A Q - C Quality of Living Active Quality of Living Active Quality of Living Enjoyment of daily Enjoyment of running, Enjoyment of sports, activities. swimming, P E , etc. swimming, P E , etc. Distress Passive Quality of Living Teenage Quality of Feelings about asthma Enjoyment of reading, Living • watching T V , etc. Enjoyment of teenage social activities. Distress Feelings about asthma Distress symptoms. Feelings about asthma symptoms and social Severity impact. Frequency of asthma symptoms. Severity Frequency of asthma symptoms. Reactivity Awareness of environmental triggers. 26 make the Q O L instrument more responsive to changes in H R Q O L . The P A Q L Q was developed according to guidelines that have been used in the construction of a dozen validated disease specific quality of life instruments. 8 3" 8 4 The following are some of the objectives of the questionnaire: • reflect areas o f function that are important to children with asthma • include both physical and emotional function • be reproducible when the clinical state is stable • be responsive to changes that are important to the patient even i f the changes are small • be valid, that is, actually measure H R Q O L in children S T R U C T U R E The interviewer-administered form of the questionnaire has 23 items that cover three domains of quality of life: activity (n=5), symptoms (n=10), and emotional function (n=8). Each item of the P A Q L Q is evaluated using one of the seven-point scales that measure the degree and frequency of asthma symptoms, impairment of activities, and limitation of emotional function. The minimum scores of each item in each domain is one, which indicates maximum degree o f asthma-related symptoms and maximum impairment of activities or limitation of emotional function. The maximum score of each item in each domain is seven, which indicates no degree o f asthma-related symptoms and no impairment o f activities or limitation of emotional function. The overall H R Q O L 27 score is the mean score of each domain. . A self-administered version of the P A Q L Q with the same number of items is also available. However, the measurement properties of this version has not yet been evaluated. In addition, the P A Q L Q has a component that can be administered to parents called the Pediatric Asthma Caregivers Quality of Life Questionnaire ( P A C Q L Q ) . Guyatt et al. have reported that additional information can be gained about children's H R Q O L by parents of children 11 years old or younger who are administered the P A Q L Q . However, in children greater than 11 years, parents can provide little information beyond what is provided through questioning the child directly. 7 3 2.2.5.1 P S Y C H O M E T R I C P R O P E R T I E S Juniper et al. evaluated the discriminative and evaluative properties o f the P A Q L Q in a nine-week prospective study with a cohort of 52 children. The children enrolled in the study had two, four-week study periods (week 2-5 and week 6-9). A s they progressed through the study periods, the children were assessed three times; at week 1, 5 and 9. A t each assessment, the children were administered the P A Q L Q , the Feeling Thermometer, and a clinical asthma control questionnaire. Spirometry was also measured at each assessment period. When the study was completed, children were classified either 28 as having stayed the same (Group A ) or changed (Group B) by one o f three methods shown in Table 4. Agreement between the different methods was calculated using a kappa statistic. The overall Q O L change within subjects was 0.79 (p < 0.001 using a paired t-test). The mean difference in Q O L score between the beginning and the end of the treatment period was also compared between the group that changed and the group that did not change, using an unpaired t-test. The mean change in H R Q O L score in the population that changed was 0.79 compared to 0.10 in subjects that remained stable (p < 0.0001). A responsiveness index was also calculated from the minimal important difference score using the mean difference in score in those who scored -3, -2, +2, or +3 on the global rating of change as the minimal important difference and the pooled within-subject standard deviation from both Groups A and B . The responsiveness index 9 3 for overall quality o f life was reported to be 0.59. The authors concluded that the P A Q L Q was responsive to within-subject change in quality of life over a four-week period. In addition, they reported that P A Q L Q scores correlated moderately with asthma control, pVagonist use, and the Feeling Thermometer,8 5 a generic quality of life instrument (see Table 5). The responsiveness index, however, may not be accurate because the methods may have been biased. The investigators used three methods to distinguish patients who changed (Group B) or stayed the same (Group A ) . However, the kappa (K) statistic of the inter-29 Table 4 Methods of Classifying Change In Patients Method Description Global Rating of Change 8 6 (Patient Rated) If patients scored -1, 0, or +1, they were considered to have stayed the same and i f they scored between -7 and - 2 or between +2 and +7 they were considered to have changed. Global Rating of Change 8 6 (Caregiver Rated) If the caregiver scored -1, 0 or +1, on their perception of whether the child's asthma symptoms have changed, the child was considered stable, for all other scores the child was considered to have changed. Clinical Evaluation Using only clinical data (asthma control score, spirometry, peak flow rates, p-agonist use) one of the investigators classified the patients as stayed the same or changed. 30 Table 5 Pearson Correlation Coefficients Showing Cross Sectional Construct Validity Asthma Quality of Life Symptoms Activities Emotions Clinical Asthma Clinical Asthma Control -0.61 -0.62 -0.37 pVagonist Use -0.51 -0.49 -0.30 Generic Quality of Life Feeling Thermometer 8 3 0.41 0.53 0.36 31 observer ratings of change was only 0.2, which is considered low (K ranges from 0, considered no better than expected by chance, to 1, considered perfect agreement).8 7 In other words, the inter-observer agreement was low. Thus, it is not clear which patients truly experienced a clinical improvement or worsening of their condition. Furthermore, it was decided only after the study was complete that only one of the three methods, the patient s Global Rating of Change, was to be used to classify change of the patients' true clinical status. Since this decision was made after the study was complete, the method used to calculate the index could have been biased. Furthermore, a commonly used index of instrument responsiveness, the effect size, has not yet been reported for the P A Q L Q for patients with moderate changes in clinical status or for patients with large changes in their clinical status. 2.2.6 USING PATIENT SPECIFIC ITEMS IN H R Q O L INSTRUMENTS T O I M P R O V E RESPONSIVENESS Most H R Q O L instruments consist of a standard set of items designed to evaluate the impact of illness on a person's health-related quality of life. Since these instruments are designed to evaluate H R Q O L in groups of patients, the items are neither specific nor individualized for each patient. Some H R Q O L instruments may assess a patient's ability to perform a particular function that may or may not be important to the patient or essential for the conduct o f day-to-day activities. Items that may not be relevant to a patient may reduce the responsiveness of the instrument. For example, an item may 32 ask a patient, " H o w has asthma affected your ability to swim?" in order to assess the impact of a patient's disease on his or her physical function. I f swimming were not an important activity for the patient to participate in, then the effect of a clinical improvement in health status such that the patient was able to more actively engage in swimming may not be significant for the patient. It has been reported that patients can generate items for H R Q O L that may be more relevant than clinician generated items. 8 8 Some instruments, like the P A Q L Q have items that patients generate. It is hypothesized that a patient-specific instrument would improve the relevance o f items to patients, and be more responsive to changes in a patient's clinical status. For example, i f an instrument were dynamic in structure and were capable of assessing those unique characteristics important to each individual's H R Q O L domains, then the instrument should be more sensitive to changes in clinical status compared to an instrument that includes items that are not relevant. In order to explore this idea, hypothesis-testing o f asthma-specific H R Q O L questions was begun. When referring to these questions collectively, the acronym Q O L i F (Quality of Life Index for Families) w i l l be used. Although the Q O L i F is not a H R Q O L instrument, it has a dynamic structure, which can be used to test this hypothesis. The Q O L i F consists o f interactive questions that first assesses patients' preferences before generating relevant questions. The Q O L i F is designed to explore whether or not individualized items can improve their responsiveness to clinical change on 33 physical functioning, social functioning, and role functioning. The Q O L i F (shown in Appendix 5) consisted of seven sections. The first section is a list o f physical activities, social activities, and role functions that the investigators use to help the children identify items that he or she performs. The items have been designed to reflect activities commonly performed by children living in Canada. Section 2 to 4 respectively, consists of the physical domain, social domain, and role function domain questionnaires for the parent or guardian. Section 5 to 7 respectively, consists of the physical domain, social domain, and role function domain questionnaires for the child. After the child identified items that he or she performs, the investigator transcribes these items into the appropriate domains of the questionnaires, which are then administered to the parent and the child. A s shown in Appendix 5, all items of the Q O L i F consist of a seven-point likert scale. Both parents and children respond to the questionnaires by marking their answers directly on the form provided. Parents are instructed to help the children answer the questions themselves, not to prompt the child, and not to influence the child's responses. 2.2.7 T H E N E E D T O E V A L U A T E RESPONSIVENESS O F H R Q O L INSTRUMENTS Studies have shown that H R Q O L measures are sensitive to change in groups of patients and are as sensitive or more sensitive than many traditional measures, such as 34 performance tests, or laboratory evaluations of disease activity. Responsiveness, which is also referred to as "sensitivity," is an important psychometric property of H R Q O L instruments because many studies that use these instruments require measurements to be made in populations over periods of time. Responsiveness, is a property that can help researchers and clinicians interpret clinically important change in H R Q O L measures. It is possible that statistically significant change over time may not necessarily represent clinically important change. A measure of responsiveness can help clinicians and researchers of H R Q O L instruments interpret numerical results of H R Q O L measurement scores in relation to benchmark scores associated with various degrees of clinical change. Furthermore, an index of responsiveness can be used to determine the statistical power of a t r ia l . 9 0 Several indices for measuring the responsiveness of a H R Q O L instruments have been proposed, although no gold standard exists. 8 9" 9 0 These methods include the effect size, 9 1 standardized response mean, 9 2 relative eff ic iency, 8 9 and Guyatt's Index. One of the more commonly reported indexes o f responsiveness is the effect size. The use of effect size calculations has been well accepted in the social and behavioural sciences. 9 4 The effect size is calculated by taking the difference between means before treatment and after treatment and dividing by the standard deviation o f the same measure before treatment as shown in Equation 1. In general, a large effect size of 0.8 or more 35 indicates high sensitivity to change. A moderate effect size of 0.5 to 0.2 is moderate, and an effect size less than 0.2 is considered small . 9 5 The standardized response mean and the relative efficiency index are similar to the effect size. Studies in the past that have examined the responsiveness of quality of life instruments have obtained similar results regardless of which method was used. E q u a t i o n 1 Effect Size Ca lcu la t ion ES = ( m - n o ) rJo ES = Effect Size jo-o = mean before treatment \i\ = mean after treatment o"o = standard deviation before treatment Guyatt's Index measures responsiveness as the ratio between the minimal clinically important difference (MCID) divided by the square root of twice the mean square error in stable subjects. 36 2.3 O B J E C T I V E S Thus, there is a need to evaluate the incidence of inappropriate use o f medication in pediatric patients admitted to hospital for asthma. Furthermore, valid, reliable, and responsive instruments are needed to evaluate the benefits of pharmacological treatments on patients with asthma. A n estimate of the frequency of drug-related hospital admissions in pediatric patients with asthma and an understanding of the causative factors associated with these admissions would provide data for clinicians and health policy decision makers to target resources at preventing these problems in the future. A better understanding of the measurement properties of health related quality of life instruments for patients with asthma would help clinicians and researchers better interpret the numerical values of health related quality of life measures in relation to patients' clinical status. The objectives of the study were the following: (1) evaluate the frequency of drug-related hospital admission in pediatric patients with asthma (2) evaluate the responsiveness o f the P A Q L Q to change in patients' clinical status using the effect size index of responsiveness (3) evaluate the merit of an individualized approach to H R Q O L assessment 37 3. M E T H O D S The study consisted of two components, the evaluation of drug-related hospital admissions, and the evaluation of health-related quality of life instruments. The two parts of the study were conducted concurrently. 3.1 E V A L U A T I O N O F D R U G - R E L A T E D H O S P I T A L A D M I S S I O N S To estimate the frequency of drug-related hospital admissions in the pediatric patient population, patients newly admitted to hospital with symptoms of acute asthma were recruited. On enrollment, data were collected and evaluated using a method that has been used by Hallas et al2' 5 1 ~ 5 4 in several previous studies. B y recruiting patients with symptoms of acute asthma, this study focused primarily on drug-related hospital admissions caused by therapeutic failures rather than adverse drug reactions. 3.1.1 P A T I E N T R E C R U I T M E N T Between August 11th, 1996 and July 15th, 1997, children between five and 17 years of age with asthma or asthma-related symptoms were recruited from Children's and Women's Health Centre of British Columbia ( C W H C B C ) ; the Children's Centre, at Mount Saint Joseph Hospital (MSJ); and Burnaby Hospital. C W H C B C is the primary treatment, research and teaching hospital of pediatric residents of the province of British Columbia. Children less than five years of age were not included because the diagnosis of asthma is less clear in this population and the therapeutic approach outlined in both 38 the Canadian and International asthma treatment guidelines are more explicit in patients five years and older. 9 6 Each day, a registered nurse whose position was: Clinical Quality Advisor, Quality Promotion, at C W H B C reviewed all the hospital admission records and reported those children who met the inclusion criteria shown in Table 6 to the investigator. This nurse had access to all the hospital admission records. The list of inclusion criteria was given to the nurse prior to the start o f the study. The nurse was instructed to report any child who was admitted to hospital with a diagnosis of asthma or asthma-related symptoms noted in the admission history of the medical chart. The symptoms of asthma include episodes o f wheezing, shortness of breath, chest tightness, and coughing. The nurse reported the name of the child to the investigator i f the admitting diagnosis on the child's health record included any of these symptoms. Once a child's name was reported to the investigator, the investigator confirmed the inclusion criteria by examining the child's health record, or speaking with the child's doctor(s), nurse(s), and other members of the healthcare team involved in the care of the patient. A n appointment was then made to meet with the child and the parent or guardian to invite them to participate in the study. A t the appointment, the purpose of the study was described. Each child and his/her parent was provided with a consent form and had 24-36 hours to decide whether or not to participate in the study. Parents who agreed to 39 participate and those children who were 12 years of age or older signed the consent form (Appendix 6). Tab le 6 Inc lus ion C r i t e r i a The following is a list of inclusion criteria that was used to select those pediatric patients that could be enrolled in the study. This list of criteria was made available to the nu.rse that reported admissions to the investigator prior to the start of the study. In addition, this list was posted in the medical wards where the study occurred. • Age between 5 to 17 years at the time of admission • Admission to hospital ward with a diagnosis of asthma or asthma-related symptoms. • N o symptoms o f any serious concomitant diseases such as cancer, A I D S , or coma • N o symptoms of any medically diagnosed abnormal psychological conditions, which may impair the patient's ability to communicate or answer health-related quality of life instruments. 40 3.1.2 SAMPLE SIZE ESTIMATE The goal was to recruit 61 patients, a number which was estimated to equal the minimum sample size for both components of the study. To determine sample size for estimating the frequency of drug-related hospital admissions in the pediatric patient population admitted to hospital with asthma, the true population proportion of drug-related hospital admissions was estimated to be between 5% and 20%. This range was based on a recent meta-analysis, 4 6 which estimated that the frequency of drug-related hospital admissions in the general population is between 2 and 21% (see Section 2.1.3). It was expected that the frequency of drug-related hospital admissions would be relatively high. Thus, to be conservative, a sample size was estimated, based on the upper end o f the range and using Equation 2. It was estimated that 61 patients would be sufficient to provide a 95% confidence interval o f ± 10% around an estimated population proportion (IT) of 20% for drug-related admissions, as shown in Table 7. Using the same equation, it was estimated that at least 21 patients would be required to obtain a reasonable estimate of the responsiveness of the quality of life instruments, as described in Section 3.2. Equation 2 Sample Size Estimate For A Population Proportion N = n(i-n)(Za/2/ci) 2 N = the sample size IT = the population proportion Z = the standard normal deviate CI = the desired confidence interval 41 Table 7 Sample Size Estimates For 95% Confidence Interval The numbers in the second and third columns show the sample size needed for the 95% confidence interval to be ± 5% or ± 10% respectively of the estimated population proportion. Estimate of Population Proportion (IT) 95% Confidence Interval ± 5 % ± 10% 5% 73 19 10% 138 36 2 0 % 246 61 30% 323 81 40% 369 92 50% 384 96 42 Over a 12-month period, it was expected that approximately 75 patients would be enrolled. Past records were evaluated for the apparent frequency of asthma-related admissions. These records had indicated that, in 1995, 150 children less than 17 years of age had been annually admitted and discharged from B C C H and the Children's Centre located at M S J . Approximately half of those children were less than five years of age. Therefore it was expected that between 61 and 75 patients who met the inclusion criteria would be enrolled over the 12 month study period. 3.1.3 D A T A C O L L E C T I O N After consent was obtained, data related to the child's admission were gathered from three sources; (1) the patient's medical record from the hospital; (2) interviews with the patient and the family; and (3) interviews with the patient's professional medical staff, including the pediatrician, specialist, nurse, pharmacist, and other members of their health care team. Using the form shown in Appendix 7, the following data were gathered: • Medication history prior to admission • Medication compliance • History of medical problems including allergy • History of hospital admissions and doctors' visits • Frequency and severity of asthma symptoms • Family history of asthma and atopy • Environmental exposure to asthma trigger factors • Abi l i ty to perform normal activities of daily l iving, including school, sleep, and social functioning • Peak expiratory flow rate (PEFR) of the child at hospital admission • P E F R of the child at hospital discharge or as soon after discharge as was available. 43 The interviews placed a particular emphasis on the symptoms on admission, current medication use, medication history and extent of compliance with medications. For example, each child and his parent or guardian was asked to describe the events that took place prior to the hospital admission, the child's previous medications, the method of administration, and signs and symptoms of respiratory distress that occurred prior to admission. 3.1.4 D E T E R M I N A T I O N O F D R U G - R E L A T E D HOSPITAL ADMISSION A team of experts in asthma care evaluated the relation between hospital admission and concurrent therapy using Hallas' algorithm, with some modification. 3.1.4.1 H A L L A S ' A L G O R I T H M Hallas' algorithm is a three-step procedure that examines first, the relation between a drug event and an adverse drug reaction and the drug event and a dose-related therapeutic failure; second, the role of the suspected symptoms to hospital admission; and third, the degree that each drug event was avoidable. To characterize the relation between drug intake and adverse drug reaction, the criteria shown in Table 8 are used. To assign causality of dose-related therapeutic failure, the criteria shown in Table 9 are used. Next, the suspected symptoms' significance for the hospital admission are evaluated using the criteria shown in Table 10. 44 Table 8 Criteria Used to Characterize the Relation Between Drug Intake and A D R 2 i . Presence of a known drug reaction or toxic reaction i i . Presence of a reasonable temporal relation between the commencement of drug therapy and the onset of the adverse reaction i i i . The adverse reaction disappeared upon discontinuation or dose reduction of the drug iv. The symptom or event could not be explained by any other known condition or predisposition of the patient v. ' The symptoms reappeared upon re-exposure or laboratory tests showed toxic levels or drug-induced metabolic disturbances that explained the symptoms "Definite " causal relation. A l l five criteria are satisfied. "Probable " causal relation. Criteria (i), (ii), (iii) and (iv) are satisfied. "Possible " causal relation. Criteria (i), (ii), and (iii) are satisfied. " Unlikely/Unevaluable " causal relation. The relevant information required for evaluation could not be obtained, the temporal sequence was atypical, or other conditions or dispositions are considered far more likely to have caused the symptoms. The relation was not rated higher than "possible" i f the adverse event occurred previously without relation to drug treatment or was an accentuation of symptoms already present before the start of drug therapy. 45 Table 9 Criteria Used to Characterize the Relation Between Drug Intake and T F 2 i . Symptoms of the disease are known to reappear at insufficient doses i i . The symptoms were not likely to have been caused by a progression of the disease i i i . A reasonable temporal relation between the start of inadequate dosage and the appearance of symptoms iv. The symptoms resolved upon adjustment to an adequate dose v. N o other condition present could explain the symptoms v i . Drug levels were clearly below the therapeutic range or there was clear evidence of intake of an insufficient dose "Definite " causal relation. A l l six criteria are satisfied. "Probable " causal relation. Criteria (i), (ii), (iii), (iv) and (v) are satisfied. "Possible " causal relation. Criteria (i), (ii), (iii) and (iv) are satisfied. "Unlikely/Unevaluable " causal relation. The relevant information required for evaluation could not be obtained, or the temporal sequence was atypical, or other conditions or dispositions are considered far more likely to have caused the symptoms. 46 Table 10 Significance For Hospital Admission 2 Dominant The suspected symptoms were the main reason for admission, and no other symptoms contributed significantly. Partly Contributing The suspected symptoms played a substantial role in admission, but other factors also contributed significantly. Less Important The suspected symptoms played a minor or uncertain role, and the patient would probably have been admitted without them. Not Contributing Other symptoms/circumstances were the main reason for hospitalization. 47 In each case where there is a "definite" or "probable" causal relation between drug intake and the drug event, and in which the symptoms are "dominant" or "partly contributing" to the hospital admission, a further evaluation is made as to whether the event could have been avoided by appropriate measures taken by health service personnel, as described in Table 11. 3.1.4.2 E X P E R T P A N E L A S S E S S M E N T / E V A L U A T I O N To perform the evaluation, a panel consisting of two clinical pharmacists (one Ph.D., one post-graduate Pharm.D trained) and one registered nurse all trained in the management of asthma met face-to-face during three eight-hour sessions. Panel members evaluated each case based on all the collected data for each patient. The data were presented to each panel member using a standardized case report. Furthermore, each patient's medical chart was also available. Although the experts had already been familiar with the The National Asthma Education and Prevention Program Expert Panel Report 2 Guidelines For the Diagnosis and Management of Asthma from the National Heart, Lung and Blood Institute ( N H L B I ) o f the National Institutes of Health and the most recent Canadian asthma treatment guidelines, the reports were also made available to the panel members during their evaluation. 3 2" 3 3 Each panel member read each case history individually and the panelists openly discussed each case before rendering a decision about each step of 48 Table 11 Classification of Avoidable Admissions Definitely Avoidable The drug event was due to a drug treatment procedure inconsistent with present day knowledge of good medical practice or was clearly unrealistic, taking the known circumstances into account. Possibly Avoidable The prescription was not erroneous, but the drug event could have been avoided by an effort exceeding the obligatory demands. Not Avoidable The drug even could not have been avoided by any reasonable means, or it was an unpredictable event in the course of treatment fully in accordance with good medical practice. Unevaluable The data for rating could not be obtained or the evidence was conflicting 49 the Hallas algorithm. However, each panel member formed his or her own conclusion and the panel members were not required to reach a consensus. Each case was first evaluated for the relation between drug intake and adverse drug reaction ( A D R ) . The relation between drug intake and A D R or D T F in each case was classified according to the criteria shown in Table 8 and Table 9. However, a modification was made to Hallas' algorithm in relation to the assessment of dose-related therapeutic failure. In Hallas' previous studies, a D T F was defined as an absence of therapeutic response that could be linked causally either to a prescribed dose that was too low, to drug non-compliance, recent dose reduction/discontinuation, interaction, or inadequate monitoring. Non-prescription of a drug was not considered to represent DTFs . In the present study, Hallas' algorithm was modified, and non-prescription of a drug was included in the classification of dose-related therapeutic failures. In addition to this modification, an emphasis was made to the panel related to interpretation o f Criterion 5 of the algorithm. Criterion 5 of Hallas' classification o f D T F is "no other condition present could explain the symptoms." The panel was instructed to interpret this statement to mean "the development of the acute symptoms could not be explained by a recent or concurrent medical condition." With this interpretation, this criterion was not satisfied i f the patient had a recent or concurrent medical condition 50 that could have explained the acute symptoms of asthma on hospital admission. If there was any evidence of a respiratory tract infection, panel members were instructed to score this criterion as "false." Since it has been estimated that 80 to 85 % " of children's asthma exacerbations are triggered by upper respiratory tract infections, the purpose of the explicit reference to respiratory tract infections was to reduce the chance that the expert panel would neglect to consider a respiratory tract infection as a potential factor contributing to a patient's symptoms on hospital admission. Following evaluation of the relation between drug intake and the A D R or D T F , the suspected symptoms' significance for the hospital admission was evaluated according to the criteria shown in Table 10. For "definite" and "probable" drug events in which symptoms were "dominant" or "partly contributing" to the hospital admission, a third evaluation was made as to whether the event could have been avoided by appropriate measures taken by the health service personnel as described in Table 11. During the evaluation of drug-related hospital admissions, the investigator made the hospital health records o f each patient available to the panel members for further reference. The final result for each criterion of Hallas' algorithm was based on the majority vote of the three panel members. Therefore, for each criterion evaluated, the result was either positive or negative—ties were not possible. 51 3.1.5 COMPARISON O F PATIENTS' D R U G THERAPIES W I T H T H E R E C O M M E N D A T I O N S O F T H E NIHLBI GUIDELINES After the formal evaluation o f drug-related hospital admissions by the panel, the investigator reviewed the results of the expert panel's evaluation together with all data collected for each case to examine the extent the patients' drug therapies were consistent with the National Asthma Education and Prevention Program Expert Panel Report 2 Guidelines For the Diagnosis and Management of Asthma. The data collected about patients' drug therapies were subjective data based on patients, parents of patients, and physicians' reports of medication use. Objective evidence of patients' actual medication use was not available. In each case, the investigator estimated the patient's chronic asthma severity prior to the exacerbation based on their reported chronic symptoms (Appendix 8) and types of prescribed medication. Patients were classified as "mild-intermittent," "mild-persistent," "moderate," or "severe" according to the classification system shown in Table 12, which has been incorporated from the Guidelines. Where there were insufficient data about patients' reported symptoms, an estimate of severity was made by considering the types of medications the patient was prescribed. However, in cases where it was not possible to categorize the patients' severity because data were insufficient, patient's symptoms were classified as "non-determinable." 52 Table 12 Classification of Asthma Severity3 2 Clinical Features Before Treatment Symptoms Nighttime Symptoms Lung Function STEP 4 Severe Persistent Continual Symptoms Limited physical activity Frequent exacerbations Frequent FEV, or PEF < 60% predicted PEF variability >30% STEP 3 Moderate Persistent Daily symptoms Daily use of inhaled short-acting pVagonist Exacerbations affect activity Exacerbations > 2 times a week' may last days > 1 time a week FEV, or PEF > 60 % <80% predicted PEF variability > 30% Symptoms > 2 times a week but < 1 time a day Exacerbations may affect activity STEP 2 M i l d Persistent > 2 times a month FEV, or PEF > 80% predicted PEF variability 20-30% STEP 1 M i l d Intermittent Symptoms < 2 times a week Asymptomatic and normal P E F between exacerbations Exacerbations brief (from a few hours to a few days); intensity may vary < 2 times a month FEV, or PEF > 80 % predicted PEF variability <20% The presence o f one of the features of severity is sufficient to place a patient in that category. A n individual should be assigned to the most severe grade in which any feature occurs. The characteristic notes in this figure are general and may overlap because asthma is highly variable. Furthermore, an individual's classification may change over time. Patients at any level of severity can have mild, moderate, or severe exacerbations. Some patients with intermittent asthma experience severe and life-threatening exacerbations separated by long periods o f normal lung function and no symptoms. 53 The guidelines indicate appropriate treatment for the chronic management of asthma symptoms and for acute episodes for each classification. Based on each patient's classification, a determination was made about whether or not each patient had "inadequate treatment." • Chronic asthma management: A patient was considered to have had "inadequate treatment" of chronic asthma i f drug therapy indicated by the guidelines for the chronic treatment of asthma was not reported in the patient's drug regimen in the last 3 months; or i f the patient, parent, or physician reported that the indicated medication was in the regimen but the patient was non-compliant in using it. • Acute asthma management: A patient was considered to have had "inadequate treatment" i f drug therapy indicated by the guidelines for treatment of the acute episode was not reported in the patient's drug regimen; or i f the patient, parent, or physician reported that the indicated medication was in the regimen but that the patient was non-compliant in using it. For example, i f a patient had "mild-persistent" asthma, but did not report regularly scheduled inhaled corticosteroids in their regimen, then the patient was considered to have had "inadequate treatment." Or i f oral steroids were indicated by the guidelines for the management of the patient's acute exacerbation, but the patient did not report having it in the regimen, then the patient was also considered to have "inadequate treatment." 54 "Inadequate treatment" was not considered present i f the patient received drug therapy that was consistent with the recommendations of the Guidelines. In some cases where data about a patient's history of symptoms were insufficient for the investigator to determine whether the patient received drug therapy appropriate for the patients' level of severity, a "not-determinable" designation was made about the presence of "inadequate treatment." In general, a patient was considered to have had "inadequate treatment" i f the patient or parent did not report receiving drug therapy for the chronic or acute asthma in accordance with the Guidelines. Since objective information about prescribed drug therapy and compliance were not obtained, the estimates of inadequate treatment were approximations. The investigator also examined patients' reported evidence of non-compliance with long-term control and quick-relief medications. During the interview, the investigator asked each patient the following three general questions related to compliance: • H o w often does the child forget to take medication? • Does the child always take medication at the same time each day? • If he feels better, would he stop taking medication on his own? The patient and the parent were then asked to expand on the answer provided to each question. Then the investigator asked specific questions about compliance 55 regarding each medication that was reported in the regimen. Patients were considered non-compliant i f the parent, child, or physician(s) reported that the child did not take their medication(s) as directed. 3.2 E V A L U A T I O N O F H E A L T H - R E L A T E D Q U A L I T Y O F L I F E I N S T R U M E N T S The collection of pediatric health related quality of life data were performed at the same time drug-related hospital admission data were collected as described in Section 3.1. To measure the responsiveness of the P A Q L Q , C A Q , and the merit o f using an individualized approach to H R Q O L assessment in the three domains of the Q O L i F , the investigator administered the questionnaires to the patients in the hospital wards during their acute phase of asthma, and again six weeks after discharge when the patients' symptoms had improved. 3.2.1 PATIENT R E C R U I T M E N T The patients who participated in the drug-related hospital admission component were invited to participate in the evaluation of quality o f life instruments. Only those patients who could understand the age-specific questionnaires were selected. Patients who had difficulty reading or understanding English were excluded from the study. 3.2.2 S A M P L E SIZE CONSIDERATIONS To determine the sample size for estimating the responsiveness of the quality of life 56 instruments, Equation 3 and Equation 4 of Cohen's, Power Analysis for Behavioural Sciences were used. Assuming a one-tailed a is 0.05 and a correlation coefficient (p) between the first and second observation is at least 0.6, the number of patients required to detect effect sizes 0.6 or greater was 21 or fewer, as shown in Table 13. With our target sample size of 61, and based on these considerations it was anticipated that we would have enough patient to estimate the responsiveness of the quality of life instruments. Equation 3 Estimate of N For Various Effect Sizes N = (no.io)/(100d 2 ) no.io = value effect size table (Table 2.4.1 9 5) d = effect size for paired samples (see Equation 4) Equation 4 Effect Size For Paired Samples d = cU' / (1 - r ) ° 5 &»' = desired effect size r = correlation coefficient 57 Table 13 Number of Paired Observations Required (Power = 0.9) Using Cohen's 9 5 method, this table shows the number of paired observations required to detect effect sizes between 0.4 to 1.0, as shown in the first row. The number of paired observations is dependent on the correlation between the paired observations. The number of paired observations based on correlations between 0 and 0.8 are shown. A l l estimates have been based on 90% power. ES 0.4 0.5 0.6 0.7 0.8 0.9 1.0 p = 0.0 109 70 49 36 28 23 19 p = 0.2 87 56 40 29 23 18 15 p = 0.4 66 42 30 22 18 14 12 p = 0.6 44 29 21 15 12 10 8 p = 0.8 23 15 11 8 7 6 5 58 3.2.3 A D M I N I S T R A T I O N O F I N S T R U M E N T S During a two-week pilot phase, the investigator administered the health-related quality of life instruments to five children who met the inclusion criteria. The pilot phase allowed the investigator to practice administering the H R Q O L instruments and to identify potential problems that might be encountered during administration. The investigator administered and scored the health-related quality of life instruments according to the guidelines described by the authors of each instrument. A n exception however, was made with the administration of the P A Q L Q , which requires parents not be present during the interview. In this study, parents were present when the interviewer administered the P A Q L Q to the children because having the parent absent during the administration of the P A Q L Q , but present during the C A Q and Q O L i F , was difficult to coordinate. Unlike the P A Q L Q , the C A Q has been designed to be administered with the parent present, to assist the child in completing the questionnaire. In one previous study the C A Q - A has been administered to groups o f up to four different children and their parent(s) together." Although it is possible that the obsequiousness bias may have been present when the P A Q L Q was administered, the effect of this bias was reduced by the investigator who ensured that the parents never prompted the children. I f a child asked for help from the parent, the investigator ensured that the parents did not influence the child's 59 response to any of the questions of the P A Q L Q by reminding the child that his or her response was all that was needed. The Q O L i F , shown in Appendix 5, was also administered by the investigator with the parent or guardian present. Similarly, i f a child asked for help from a parent or guardian, the investigator ensured that the parent or guardian did not influence the child's responses. Parents were instructed to help the children answer the questions themselves, not to prompt the child, and not to influence the child's responses. To administer the Q O L i F , the child was first asked to select from the list of physical activities, social activities, and role functions items that he or she normally performed. Each item was read aloud to each the child, and the investigator recorded the items that the child identified. After the investigator recorded the items, the child was asked to select, the "top three" most important items to them, and the "top three" least important items from the items that were initially identified. The purpose of identifying the top three most important items and the top three least important items was to compare the effect sizes to the responses of these items. After al l items were identified, the investigator transcribed each item next to each seven-point likert scale shown in each form corresponding to each domain. The parent or guardian then responded to each domain-specific questionnaire by marking their answers directly on the form. The parents' answers were not made available to the child. After the parent or guardian 60 responded to each questionnaire, the children responded to his or her own set of questionnaires. The appropriate set of age-specific health-related quality of life instruments were administered as shown in Table 14. The order that the instruments were administered within each set was randomized. The first administration occurred during the patient's stay in hospital. The follow-up administration occurred six weeks after hospital discharge in the patient's home. Patients were not shown their previous scores during the second administration of the C A Q instruments. 3.3 PRIMARY ANALYSIS The primary analysis of drug-related hospital admissions consisted of three measures. The first measure was an estimate of the population proportion in which drug events were were classified as "definite," "probable," "possible," or "unlikely/unevaluable." The second measure was an estimate o f the proportion of the population in which the suspected drug event's contribution to the admission was classified as either "dominant," "partly contributing," "less important," or "not contributing." The third measure was an estimate o f the proportion of the population in which hospital admissions were classified as "definitely avoidable," "possibly avoidable," "not avoidable," or "unevaluable." 61 Table 14 Quality of Life Instrument Administered By Age Group Age 5-6 7 8-11 12-16 17 H R Q O L Instruments P A Q L Q P A Q L Q P A Q L Q P A Q L Q Administered C A Q - A C A Q - A C A Q - B C A Q - C Q O L i F Q O L i F Q O L i F Q O L i F Q O L i F 62 For the second component of the study, the primary measures were estimates of the effect size for each domain and summary scores of the C A Q , P A Q L Q , and Q O L i F . 3.4 S E C O N D A R Y A N A L Y S I S A n estimate was made of the proportion of the study sample that had "objective" or "subjective" evidence of an upper respiratory tract infection prior to their hospital admission, evidence of non-compliance with medications, inappropriate management of their acute asthma exacerbation, inappropriate use of preventative or prophylactic therapy, and a lack o f a prescription. 3.5 S T A T I S T I C A L E V A L U A T I O N To estimate the population proportion o f drug-related events, 95% confidence intervals were calculated. Paired t-tests were used to compare health-related quality o f life mean scores measured during hospital admission to scores measured six weeks after hospital treatment. A n effect size was calculated using Equation 1 in Section 2.2.7 as an index of responsiveness for each of the instruments. A l l statistical tests were computed using SPSS for Windows™ and Microsoft Excel 97.™ Results were deemed to be significant when p was less than or equal to 0.05. 63 4. R E S U L T S The results are presented in the following three sections. Section 4.1 describes the demographic and clinical features of the patients who participated in either one or both components of the study. Section 4.2 describes the chronic and acute drug regimens of the patients in the drug-related hospital admission cohort. Section 4.3 describes the results of the evaluation of drug-related hospital admissions and Section 4.4 describes the results of the evaluation of the responsiveness o f the P A Q L Q , and Q O L i F to clinical change. 4.1 D E S C R I P T I O N O F T H E O V E R A L L S T U D Y S A M P L E Sixty-one consecutive hospital admissions were identified and reported to the investigator for evaluation. In total, 54 of the 61 children and their parents agreed to participate in the study and met all o f the inclusion criteria (Table 6). A l l parents who enrolled their children in the study and those children who were 12 years o f age or older enrolled and signed the consent form shown in Appendix 6. One parent refused to have his child participate, and six children were excluded from both components of the study by the investigator. Patients who were excluded included two children who had a diagnosis of pneumonia on admission rather than asthma, one child who had an admitting diagnosis of croup, two children who had 64 parents who could not understand or speak English, and one child who did not provide enough information for evaluation for either components of the study. The number of children who met the inclusion criteria and were enrolled each month is shown in Figure 1. The largest number of children was recruited in the month of September. Furthermore, a rise in the frequency of enrollment of children was observed in spring between January and Jufie. The number of children enrolled in the month of July included only those children admitted between July 1 s t and July 15.,th 4.1.1 D E M O G R A P H I C FEATURES O F PATIENTS IN T H E STUDY S A M P L E O f the 54 children who enrolled in the study, 36 (67%) were male and 18 (23%) were female. The mean age was 8.6 ± 3.2 years (median age, 7.8 years). The age distribution is shown in Figure 2. The difference in age between boys and girls was not statistically significant (2-tailed t-test, p = 0.917). Fifteen (28%) were Caucasian; 17 (31%) were Chinese and the rest were other minorities. Forty (74%), were from Vancouver. Furthermore, forty (74%) o f the patients were admitted to M S J . A summary o f the demographic and physical features o f the study sample is presented in Table 15. Appendix 9 shows the demographic data for each patient enrolled in the study. Each patient's height and weight and the respective percentiles are presented in Appendix 10. 65 Figure 1 Number of Children Enrolled Per Month (n=54)a 16 i 14 12 10 + i— !E O Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Month For August and July, data were collected for only half the month. 66 Figure 2 Age Distribution of Patients in the Study Sample (n=54) Age (Years) • Females • Males 67 Table 15 Age, Height, and Weight of the Patients in the Overall Study Sample8 Males Females Total Age (years) mean ± SD (n) 8.6 ± 3 . 2 (42) 8.5 ± 3 . 1 (12) 8.6 ± 3 . 2 (54) Height (cm) mean ± SD (n) 129.4 ± 2 0 . 9 (30) 114.0 ± 2 4 . 3 (12) 125.4 ± 2 0 . 9 (42) Height (percentile) mean ± SD (n) 51.0 ± 3 2 . 6 (25) 41.3 ± 2 2 . 3 (10) 48.2 ± 30.3 (35) Weight (kg) mean ± S D (n) 32.4 ± 16.7 (34) 27.5 ± 12.0 (15) 30.9 ± 15.4 (49) Weight (percentile) mean ± S D (n) 50.3 ± 35.2 (25) 43.4 ± 30.5 (12) 48.1 +33.5 (37) Total sample included 42 males and 19 females. Only data recorded in the patients' hospital medical records were included. 68 4.1.2 C L I N I C A L F E A T U R E S O F PATIENTS IN T H E O V E R A L L STUDY S A M P L E The clinical data for each patient were obtained shortly after hospital admission. Clinical respiratory system data (heart rate, respiratory rate, oxygen saturation at room air, and peak expiratory flow rate) from each patient's health record are shown in Appendix 11. Some data for some patients were not available because they were not recorded in their health records. The mean values, as summarized in Table 16, were consistent with the clinical features of acute respiratory distress. The mean peak flow on admission was 60.6 ± 22.6% of the age and weight-adjusted predicted values. This represented asthma in the moderate range as P E F R is correlated with asthma severity (Appendix 12). In addition, the mean arterial oxygen saturation in room air on admission was reduced, at 93.3 + 3.3% (normal 94-100% 1 0 0 ) . The patients had a mean heart rate of 129.9 ± 29.4 beats per minute, and all but three of the children had a heart rate higher than their age-adjusted expected value. 1 0 1 , 1 0 2 Expected heart rates in children based on age and weight are shown in Table 17. The mean age-adjusted expected heart rate of the study sample was 92.6 ± 1 1 . 5 beats per minute. The children also had an elevated mean respiratory rate of 31.3 ± 7.3 breaths per minute, which is more than two standard deviations above the mean values for children who are five years o f age and older . 1 0 3 In general, the normal respiratory rate in children is inversely related to age (see Figure 3). 69 Table 16 Mean Values of Heart Rate and PEFR on Admission of the Overall Study Sample Males Females Total Heart Rate (beats/min) mean ± SD (n) 130.0 ± 2 2 . 5 (33) 126.7 ± 4 2 . 9 (15) 129.9 ± 30.0 (48) Respiratory Rate (breaths/min) mean ± SD (n) 30.8 ± 7.2 (34) 33.5 ± 7 . 5 (15) 31.6 ± 7 . 3 (49) Room Air Oxygen Saturation On Admission (%) mean ± SD (n) 93.1 ± 3 . 3 (34) 93.9 ± 3 . 1 (15) 93.3 ±3.1 (49) Peak Flow On Admission (L/min) mean ± SD (n) 200 ± 100.8 (18) 156.7 ± 3 2 . 8 (9) 185.6 ± 8 8 . 4 (27) Peak Flow On Admission17 (% predicted value) mean ± SD (n) 60.8 ± 24.6 (14) 60.0 ± 13.2 (3) 60.6 ± 22.6 (17) Total sample included 42 males and 19 females. Only data recorded in patient charts were included. b Some values were not available where height and weight data were not available. 70 Table 17 Expected Heart Rates For Infants and Children Age Range Weight Expected Heart Rate (beats per minute) 4 - 5 years 1 6 - 1 8 kg 100 6 - 8 years 20 - 26 kg 100 1 0 - 1 2 years 3 3 - 4 2 kg 75 > 14 years > 5 0 k g 75 71 Figure 3 Normal Respiratory Rates At Rest In Relation to A g e 1 0 3 The solid line represents mean respiratory rate and the dashed line represents ± 2 standard deviations from the mean. Age (years) 72 Appendix 13 describes each patient's clinical symptoms on admission. Appendix 8 shows details of each patient's chronic symptoms of asthma before hospital admission. A s shown in the Appendices, most patients had chronic symptoms of asthma prior to hospital admission. Forty-four (82%) of the patients had a prior diagnosis of asthma and were known to have had asthma for 5.3 ± 3.4 years. O f the 14 children for whom data were available, the parents indicated that the children missed a mean of 11.5 ± 10.6 days of school due to asthma symptoms in the year prior to hospital admission. The mean duration of hospital stay was 2.6 days ± 1 . 3 days for both genders. 4.1.3 D R U G - R E L A T E D H O S P I T A L A D M I S S I O N C O H O R T In the first component of the study, 44 of the 54 patients in the study sample were able to be evaluated for drug-related hospital admissions by the expert panel. Four patients were not included i n this component o f the study because the children or parents did not provide enough data for evaluation by the panel. In these four cases, the hospital stay was too short for data to be collected. Six patients were excluded from the first component of the study because they were diagnosed with asthma for the first time and thus did not have a previous history of asthma. The mean (±SD) age of the 44 patients in the study sample was 8.6 ± 3.1 years (median age, 8.1 years). Twenty-eight (64%) were males and 16 (36%) were females. Twelve (27%) were Caucasian; 15 (34%) were Chinese and the rest were other 73 minorities. The mean (±SD) height was 124.0 ± 2 3 . 2 cm (n = 34). The mean (+SD) percentile height was 46.1 ± 29.5 percentile (n = 29). The mean (±SD) weight was 30.3 ± 14.5 kg (n = 41). The mean (±SD) percentile weight was 46.3 ± 33.0 percentile (n = 31). The mean (±SD) heart rate was 129.2 ± 3 1 . 7 beats per minute (n = 40). The mean (±SD) respiratory rate was 30.9 ± 7.1 breaths per minute (n = 41). The mean (±SD) room air oxygen saturation on admission was 93.3 ± 3 . 0 % (n = 41). Furthermore, the mean (±SD) P E F R on admission was 169.0 ± 67.4 litres per minute (n = 24), which was estimated to represent 61.9 ± 16.2 % o f predicted (n = 14). 4.1.4 P A T I E N T S D I A G N O S E D W I T H A S T H M A F O R T H E F I R S T T I M E D U R I N G T H E H O S P I T A L A D M I S S I O N Five of the six patients diagnosed with asthma or reactive airways disease for the first time during the hospital admission were males. The mean (±SD) age of these six patients was 6.7 ± 2.6 years. A l l six patients were from Vancouver and were admitted to M S J . Two of the six patients had a family history of asthma, and two others had a previous history of eczema. Based on parents' reports, the children had a mean (±SD) o f 1.7 ± 0.8 days of asthma-related symptoms prior to being admitted to hospital. The patients' mean (±SD) height was 118.9 ± 9.4 cm. Three of the six were above the 50 t h percentile in height. The patients' mean (±SD) weight was 23.8 ± 5.3 kg. Four of the six were above the 50 t h percentile in weight. The mean (±SD) body temperature on admission was 36.7 ± 0.6° C . The mean (± SD) respiratory rate was 35.0 ± 9 . 1 breaths per minute, the mean 74 (±SD) heart rate was 138.7 ± 7.7 beats per minute, and the mean (±SD) arterial oxygen saturation in room air was 92.7 ± 3.9%. 4.1.5 H E A L T H - R E L A T E D Q U A L I T Y O F L I F E A S S E S S M E N T C O H O R T In the second component of the study, 36 patients completed one or more of the health-related quality of life questionnaires. Section 4.4 describes the study population of the second component of the study, and the results of the evaluation of the responsiveness of the P A Q L Q , C A Q , and Q O L i F to clinical change in this population. 4.2 T H E C H R O N I C A N D A C U T E D R U G R E G I M E N O F T H E P A T I E N T S I N T H E D R U G - R E L A T E D H O S P I T A L A D M I S S I O N C O H O R T The panel evaluated 44 of the 54 patients in the study sample for the relation between medication use and hospital admission. Appendix 14 shows a list of the medications that the patients in this study sample reported to be taking before hospital admission. The types of medications the patients reported in their regimen for the management of their chronic asthma before hospital admission are presented in Section 4.2.1. The types of medications the patients reported in their regimen for the acute exacerbations are presented in Section 4.2.2. 75 4.2.1 MEDICATIONS T A K E N F O R T H E C H R O N I C M A N A G E M E N T O F A S T H M A Figure 4 shows a distribution of the number o f prescription medications children reported to be in their regimen for the chronic management of their asthma. The number of chronic medications included both "regularly scheduled" medications and medications taken "as-needed" for symptoms. The median number of chronic medications was one. Twenty-one o f 44 patients (48%) did not report having any chronic medications in their regimen prior to their hospital admission. The types of medications the patients reported in their regimen are shown in Figure 5. Figure 6 shows a distribution of the number o f regularly-scheduled medications that the children reported in their regimen for the chronic management o f asthma. The parent or the child reported that six of these medications were not used or were 76 Figure 4 Distribution of Prescription Medications Prescribed For the Chronic Management of Asthma As Reported By Patients or Parent(s) of Patients The number of prescribed medications represents the sum of the number of medications taken on a regular basis and as-needed for symptoms. Included in the figure are ten medications that were prescribed but were not taken or not taken as directed. 77 Figure 5 Types of Medication Prescribed For the Chronic Management of Asthma As Reported By Patients or Parent(s) of the Patients salbutamol 47.6% budesonide 26.2% 78 Figure 6 Distribution of Regularly-Scheduled Medications Prescribed For the Chronic Management of Asthma as Reported by the Patient or the Parent(s) of the Patient. The number of prescribed medications represents the sum of the number of regularly scheduled medications. Included are six medications that were prescribed but were not taken or not taken as directed by the physician. 30 25 20 c 0) '•*-> A Q . •s 1 5 0) Si E 3 Z 10 28 -44-1 2 3 Number of Prescription Medication 4 or more 79 not taken according to the instructions of the prescribing physician. The median number of medications reported in their regimen was zero. Twenty-eight children did not report having any "regularly scheduled" medications. Fourteen of the 44 children reported taking one "regularly scheduled" medication for the chronic management of asthma. Two children reported that they took three "regularly scheduled" medications. Only six of the 44 children reported taking an inhaled corticosteroid on a regular basis for the chronic management o f asthma, prior to hospital admission. Eight of the 14 children (57%) reported being prescribed an inhaled corticosteroid but did not take it regularly. The types of regularly scheduled medications that the patient reported in their regimen is shown in Figure 7. The distribution of "as-needed" medications prescribed for the chronic management of asthma is shown in Figure 8. The parent or child study participants reported that four o f these medications were not used. The median number o f medications prescribed was zero. The types of "as-needed" medications prescribed for the chronic management o f asthma is shown in Figure 9. 4.2.2 M E D I C A T I O N T A K E N F O R T H E A C U T E E X A C E R B A T I O N Some of the children were administered drug therapy in addition to the medication that they were already taking for the management of their chronic asthma. The medication taken for the acute exacerbation included increased doses of their "regularly-80 Figure 7 Types of Regular ly-Scheduled Medicat ions Repor ted by the Patient or the Parent(s) of the Patient to be in the Pat ient 's Regimen for the C h r o n i c Management of A s t h m a The types of regularly-scheduled medications prescribed are shown below. Included in the figure are six medications that were not taken or not taken as directed by the physician. 81 Figure 8 Distribution of "As-needed" Medications Reported by the Patient or Parent(s) of the Patient to be in the Patient's Regimen for the Chronic Management of Asthma Included in the figure are four medications that were prescribed, but were not taken. 30 82 Figure 9 Types of "As-needed" Medications Reported by the Patient or the Parent(s) of the Patient to be in the Patient's Regimen for the Chronic Management of Asthma Included in the figure are four medications reported in the patients' regimen but were not taken at all. 83 scheduled" chronic medications and different drugs taken specifically for the acute exacerbation. Thirty-one of the 44 patients (70%) reported that they increased the dose of their regularly scheduled chronic medications or reported that they took medications in addition to their "regularly-scheduled" chronic medications. In 14 of these 31 cases (45%), the children reported that they increased the dose of chronic medication and did not add additional drugs. The distribution of the number of medications that the children reported that they took for the acute exacerbation is presented in Figure 10. A s shown, 13 patients (30%) did not report increasing the dose of their chronic medications or add additional therapy for their acute exacerbation. The types of medications that the children reported taking specifically for the acute exacerbation, other than what they were already taking for the chronic management of their asthma is shown in Figure 11. 4.3 E V A L U A T I O N O F D R U G - R E L A T E D H O S P I T A L ADMISSIONS The results of the panel evaluations to determine the relation between drug intake and the presence of an adverse drug reaction or therapeutic failure, the significance o f the symptoms for hospital admission, and the degree that each admission was deemed avoidable for each of the 44 cases is shown in Appendix 15. Appendix 16 shows a summary o f the events leading up to each hospital admission for the 44 cases that were evaluated by the expert panel. The method that the panel used and the makeup o f the panel have been described in Section 3.1.4. 84 Figure 10 Distribution of Number of Medications that Patients Reported Taking for the Acute Episode Figure 11 Types of Medica t ions that the Patients Repor ted T a k i n g for the Acute Episode salbutamol 65.9% 2 3% beclomethasone 2 3% 13.6% 86 O f the 44 patient admissions that were evaluated, 37 (84%, 95% CI = 73-95%), were found to be "definitely" drug-related (Figure 12). A l l 37 cases of drug-related hospital admissions were considered to be therapeutic failures. N o adverse drug reactions were found. Furthermore, the panel concluded that in all 37 cases, the symptoms of asthma were the "dominant" reason for admission, and that they were all "avoidable." Seven of 44 admissions (16%, 95% CI = 5-27%) were deemed to be "possibly" drug-related by the panel. In six of the seven cases, the symptoms of asthma were judged by the panel to be the "dominant" reason for admission. In the remaining case, the symptoms were deemed to be "partly contributing" to the admission. In accordance with Hallas' algorithm, the panel did not evaluate the avoidability of hospital admission in the cases where the probability of adverse drug reaction or therapeutic failure were not deemed to be "definite." 4.3.1 E F F E C T S O F S Y M P T O M S O F URTI O N D R U G - R E L A T E D ADMISSIONS The panel reported that evidence that could have explained the symptoms was present in seven of the 44 cases o f hospital admissions evaluated. These admissions were therefore rated as "possibly" drug-related. This designation was made because of the presence of a "condition" that could have explained the symptoms. Table 18 summarizes the symptoms found by the panel to be associated with the acute exacerbation. In one case, the child had a diagnosis of bronchitis along with a diagnosis of an acute asthma 87 Figure 12 Class i f ica t ion of D R H A s Dark bars indicate the frequency of "definite," "probable," "possible," and "unlikely" therapeutic failures of the 44 cases that were evaluated by the expert panel. Light bars indicate the frequency of therapeutic failures by the investigator who considered 14 additional cases where there was evidence of a condition other than asthma that could have explained the patients' symptoms on admission. 40 i Definite Probable Possible Unlikely Likelihood of Therapuetic Failure • Evaluation By Expert Panel HSubsequent Modification By Investigator 88 Table 18 Evidence From Patients' Case Summaries of a Condition That Could Have Explained the Symptoms In the Seven Cases Deemed to Be "Possibly" Drug-related By the Panel Patient Evidence From Each Patient's Case Summary of a Condition that Could Have Explained the Symptoms Related to the Patient's the Hospital Admission 42 Diagnosis of bronchitis 43 A fever o f 3 9 ° C . 44 Since two weeks he has had sore throat- given amoxicill in but progressed to cough, wheeze and dyspnea. Chest X-ray revealed actelectasis in left lower lobe, suspected atypical pneumonia 45 Right medial lobe pneumonia; treated with intravenous cefuroxime 46 Admitted for fever and cough. Right upper lobe pneumonia, infectious contact with 2.5 years old sister 47 24 hours prior to admission he developed an apparent cold, low grade fever, discharge from nose. 48 Runny nose and cough for three days. 89 exacerbation noted in the medical chart. In another case, the child had a fever o f 39°C and no other symptoms. In three cases, patients had or were suspected of having pneumonia. In two other cases, patients had symptoms of an upper respiratory tract infection prior to admission. In these cases, despite other evidence o f drug-related factors leading to admission, criterion 5 of Hallas' algorithm was not satisfied, and in all seven cases, the panel concluded that the relation between drug intake and therapeutic failure was only "possible." On examination of patients' case summaries after the panel had evaluated the admissions, the investigator found that there was evidence o f a condition that could have explained the symptoms in 14 additional cases. The evidence in each o f the 14 cases is summarized in Table 19. In two cases, patients had reported experiencing fever prior to admission. In another case, the physician suspected pneumonia and the patient had symptoms of an upper respiratory tract infection. In the remaining cases, the physician or parents noted symptoms consistent with upper respiratory tract infection experienced by the children during the week prior to admission. Had the panel determined that the symptoms of infection reported for the children provided sufficient evidence for a condition that could have explained the symptoms on admission, then the overall evaluation for drug-related hospital admissions using Hallas' algorithm would have changed accordingly. Figure 12 shows the frequency o f drug-90 Table 19 Fourteen Additional Cases of Patients With Evidence of a Respiratory Tract Infection Identified by the Investigator. The investigator determined that the following 14 patients had evidence of a respiratory tract infection before their hospital admission. These patients had been deemed to have a definite relation between drug intake and therapeutic failure by the panel. The evidence shown for each case was taken from each patient's hospital record. Patient Evidence From Each Patient's Case Summary of A Condition That Could Have Explained the Symptoms of the Hospital Admission 1 Suspected pneumonia. Twenty-four hour cough and fever, runny nose. Fever "98.1 F , " [sic] given ibuprofen, and improved. 5 Two day history of runny nose and sore throat. 8 Asthma symptoms started with flu symptoms, coughing. 13 Three day history of U R T I 16 Cough and runny nose. 17 Runny nose 19 Sore throat, runny nose 23 Cold started five days ago. 24 Had fever two to three days ago. 32 Fever 33 Two day history of U R T I (known trigger) 34 Parents don't [sic] think that she had a cold or the flu, which started two weeks prior to hospital admission. 40 For past three days has had symptoms of cold: slight fever, cough, no runny nose. 41 Sore throat, some runny nose, cough 91 related hospital admissions; 23 of the 44 cases (52%, 95% CI = 36 - 67%) would have been considered "definite" and 21 of the 44 cases (48%, 95 % CI = 33 - 62%) would have been considered "possible" therapeutic failures. 4.3.2 PATIENTS' D R U G T H E R A P Y IN R E L A T I O N T O T H E R E C O M M E N D A T I O N S O F T H E NIHLBI GUIDELINES The investigator estimated that 16 of the 44 patients (36%) had "mild-intermittent" asthma, 15 of 44 patients (34%) had "mild-persistent" asthma, and seven of 44 patients (16%>) had "moderate persistent" asthma on a chronic basis prior to their acute episode. Six cases (14%) were classified as "non-determinable" (see Appendix 17). 4.3.2.1 M A N A G E M E N T O F C H R O N I C A S T H M A A patient was considered to have had "inadequate treatment" o f chronic asthma i f drug therapy indicated by the guidelines for the chronic treatment of asthma was not reported in the patient's drug regimen in the last three months; or i f the patient, parent, or physician reported that the indicated medication was in the regimen but that the patient was non-compliant in using it. Based on each patient's estimated level of severity and the N I H L B I guidelines, evidence of inadequate treatment of chronic asthma was found in 19 of the 44 cases (43%). Non-compliance was identified in 13 o f the 19 cases (68%) o f inadequate treatment of chronic asthma. Nine of 23 patients (39%) who were prescribed regularly scheduled medications were reported to be not compliant with therapy. 92 In most cases, patients had been prescribed inhaled corticosteroids but were not using them. Only 14 of 44 patients (32%) reported taking medications as directed on a regular basis for their chronic asthma. None of the 16 patients with "mi ld intermittent" asthma, had "inadequate treatment," and none of the 16 were reported to be non-compliant. Thirteen of the 16 patients (82%) who had "mi ld persistent" asthma did not receive daily anti-inflammatory medication as indicated by the guidelines, and thus had "inadequate treatment," as shown in Table 20. Five o f the 13 patients did not report having a regularly scheduled anti-inflammatory medication in the regimen. Eight of the 13 patients reported a regularly scheduled anti-iriflammatory medication in the regimen but were not compliant in using it. Among the seven patients with moderate persistent asthma (Table 21), six had "inadequate treatment" due to non-compliance and one patient (#38) was "non-compliant" with his long-term control medication and also did not receive influenza vaccination as indicated by the guidelines. None of the five patients in whom severity was "non-determinable," had "inadequate treatment" or "non-compliance." 4.3.2.2 M A N A G E M E N T O F A C U T E E P I S O D E A patient was also considered to have had "inadequate treatment" i f drug therapy indicated by the guidelines for treatment o f the acute episode was not reported in the patient's drug regimen; or i f the patient, parent, or physician reported that the 93 Table 20 Presence of Inadequate Chronic Treatment of Patients with "Mild-Persistent" Asthma Patient Inadequate Treatment According to the Guidelines Description of Inadequate Chronic Treatment3 1 Y E S Daily anti-inflammatory indicated but the patient was non-compliant in using it. Budesonide DPI was prescribed one year ago on twice daily dosing, but the patient misses the occasional dose. Furthermore, the patient forgets to take medication sometimes and does not always take the medication at the same time each day. When the patient feels better, the patient sometimes stops taking medication on his own. 4 Y E S Daily anti-inflammatory medication indicated but not reported to be in the regimen. The patient did not receive daily anti-inflammatory medication. The patient was also non-compliant with terbutaline sulphate M D I . The patient had been prescribed terbutaline sulphate M D I one year ago. This was the only medication he had been prescribed and no other medications were reported in the regimen. However, previous to this acute episode, the patient had not used the terbutaline sulphate M D I . 6 Y E S Daily anti-inflammatory medication indicated but the patient was non-compliant with prescribed daily anti-inflammatory due to poor inhaler technique. 12 Y E S Dai ly anti-inflammatory medication indicated but the patient did not take prescribed budesonide DPI because it was not available. 13 N D N D 19 Y E S Dai ly anti-inflammatory medication indicated but not reported to be in the regimen. The patient did not receive daily anti-inflammatory medication. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. a Descriptions of patients' drug therapies were recorded from patients' medical charts or reported by the patient, parent, or health personnel. 94 Table 20 (cont...) Presence of Inadequate Chronic Treatment of Patients with "Mild-Persistent" Asthma* Patient Inadequate Treatment According to the Guidelines Description of Inadequate Chronic Treatment" 22 Y E S The patient was in the process of weaning off the inhaled corticosteroid during the U R T I . 23 N D N D 25 Y E S Daily anti-inflammatory medication indicated but not reported to be in the regimen. The patient did not receive daily anti-inflammatory medication. 29 N D N D 31 Y E S Daily anti-inflammatory medication indicated but not reported to be in the regimen. The patient did not receive daily anti-inflammatory medication. The patient was non-compliant. Patient's reported use of medication was not consistent. Parents did not appear to be very involved in the patient's management of asthma. 40 Y E S Daily anti-inflammatory medication indicated but it was noted in the medical record that the patient had poor inhalation technique. The patient did not receive the daily anti-inflammatory medication as directed because of the poor inhalation technique. 41 Y E S Daily anti-inflammatory medication indicated but not reported to be in the regimen. The patient did not receive daily anti-inflammatory medication. 42 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses o f the prescribed daily anti-inflammatory medication because the patient was non-compliant. The prescribed anti-inflammatory medication was not used. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. " Descriptions of patients' drug therapies were recorded from patients' medical charts or reported by the patient, parent, or health personnel. 95 Table 20 (cont...) Presence of Inadequate Chronic Drug Treatment of Patients with "Mild-Persistent" Asthma 3 Patient Inadequate Treatment According to the Guidelines Description of Inadequate Chronic Treatment11 45 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses of the prescribed daily anti-inflammatory medication because the patient was non-compliant. The prescribed anti-inflammatory medication was not used. The patient was also non-compliant with salbutamol M D I . 48 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses of the prescribed daily anti-inflammatory medication because the patient was non-compliant. The prescribed anti-inflammatory medication was not used. The parent is not compliant with medication because the parent is afraid of the adverse effects. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. a Descriptions of patients' drug therapies were recorded from patients' medical charts or reported by the patient, parent, or health personnel. 96 Table 21 Presence of Inadequate Chronic Treatment with Chronic Drug Therapy in Patients with "Moderate-Persistent" Asthma Patient Inadequate Treatment According to the Guidelines Description of Inadequate Chronic Treatment" 5 Y E S " Daily anti-inflammatory medication indicated but the patient did not receive the medication as directed because the patient was non-compliant. The budesonide M D I was prescribed twice daily. However, the patient only took the medication twice weekly, despite requiring the salbutamol M D I , the beta-agonist rescue medication, three to four times daily. 10 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses of the medication as directed because the patient was non-compliant. Influenza vaccination indicated but not reported to be in the regimen. The patient did not receive influenza vaccination. 16 Y E S Daily anti-inflammatory medication indicated but the patient did not receive the medication as directed because the patient was non-compliant. The budesonide DPI was rarely used. 24 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses of the medication as directed because the patient was non-compliant. The patient was non-compliant with nedocromil sodium M D I . The patient has stopped using the nedocromil sodium M D I . 32 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses of the medication as directed because the patient could not afford to purchase the medication. 36 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses of the medication as directed because the patient was non-compliant. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. a Descriptions of patients' drug therapies were recorded from patients' medical charts or reported by the patient, parent, or health personnel. 97 Table 21 (cont...) Presence of Inadequate Chronic Treatment of Patients with "Moderate-Persistent" Asthma Patient Inadequate Treatment According to the Guidelines Description of Inadequate Chronic Treatment 38 Y E S Daily anti-inflammatory medication indicated but the patient did not receive any doses of the medication as directed because the parent was non-compliant. The parent sometimes forgets to administer the medication. Influenza vaccination indicated but not reported to be in the regimen. The patient did not receive influenza vaccination. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. "Descriptions of patients' drug therapies were recorded from patients' medical charts or reported by the patient, parent, or health personnel. 98 indicated medication was in the regimen but that the patient was non-compliant in using it. Evidence of inadequate treatment of the acute asthma episode was present in 39 of the 44 cases (95%), which are summarized in Table 22 to Table 25. In four cases, the presence of inadequate treatment was considered non-determinable and in one case, the patient was treated properly. Each patient's acute symptoms on hospital admission are shown i n Appendix 13. The actions taken by each patient, the parent, or the guardian of each patient at the first sign of symptoms related to the hospital admission are shown in Appendix 16. Appendix 18 shows which patients did not take inhaled or oral steroids for the acute exacerbation. In six of the 39 cases (14%) of "inadequate treatment", there was evidence of non-compliance with medications for the management of the acute episode. In 37 of the 39 cases, there was evidence of inadequate treatment based on the patients' histories of symptoms and severity of exacerbations. Overall, 29 of the 44 patients (66%) that were examined had a history of severe exacerbations. Twenty-six of the 44 patients had one or more previous hospital admissions. Furthermore, 14 o f the 44 patients reported that they had on average 2.4 previous hospital admissions for asthma. In 10 of the 44 cases (23%), patients failed to start any drug treatment for management of his or her acute exacerbation. In 25 of the 44 cases (57%), patients required oral corticosteroids for the acute exacerbation but did not report the medication in the regimen. Patients reported taking oral corticosteroids in only three o f the 25 cases, despite having symptoms severe enough to require hospital admission. 99 Table 22 Presence of Inadequate Acute Treatment of Patients with "Mild-Intermittent" Asthma Patient Inadequate Treatment Description of Inadequate Acute Treatment 3 Y E S Inhaled short-acting P2-agonist indicated for initial treatment but the patient did not receive any doses at al l . The patient did not receive P2-agonist because the patient did not know how to use it. The patient has had difficulty using the salbutamol M D I so the patient did not use it at al l . N o medication were administered for the acute exacerbation. 7 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 8 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 11 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 15 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 17 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 21 Y E S Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having p2-agonist in the regimen. The patient did not receive any treatment for two days prior to hospital admission. 27 Y E S Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having p2-agonist in the regimen. The patient did not receive any treatment for two days prior to hospital admission. 30 Y E S Oral corticosteroids, indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. 100 Table 22 (cont...) Presence of Inadequate Acute Treatment of Patients with "Mild-Intermittent" Asthma 33 Y E S Inhaled short-acting P2-agonist indicated for initial treatment but the patient did not report having p2-agonist in the regimen. The patient did not receive any treatment for two days prior to hospital admission. 34 Y E S Inhaled short-acting P2-agonist indicated for initial treatment but the patient did not receive any doses at all . A l l medications taken were expired. 35 Y E S Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having P2-agonist in the regimen. The patient did not receive any treatment for two days prior to hospital admission. 39 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 44 Y E S Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having p2-agonist in the regimen. The patient did not receive any treatment for two days prior to hospital admission. 46 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. 101 Table 23 Presence of Inadequate Acute Treatment of Patients with "Mild-Persistent" Chronic Severity Patient Inadequate Treatment Description of Inadequate Acute Treatment 1 Y E S Doubling the dose on inhaled corticosteroid indicated but not reported in the regimen. The patient did not receive an increased dose of inhaled steroids for seven to ten days after initial P2-agonist treatment. 4 Y E S Oral corticosteroids indicated for the severe exacerbation but the patient did not report having oral corticosteroids in the regimen. Asthma symptoms started seven days before hospital admission and the patient had an incomplete response to p2-agonist. Therefore, oral corticosteroids were indicated. 6 N D N D 12 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 13 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 19 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 22 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 23 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 25 Y E S Inhaled short-acting P2-agonist indicated for initial treatment but the patient did not report having p 2-agonist in the regimen. The patient did not receive any treatment for one day prior to hospital admission. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or the patient, parent, or physician reported noncompliance. 102 Table 23 (cont...) Presence of Inadequate Acute Treatment of Patients with "Mild-Persistent" Chronic Severity Patient Inadequate Treatment Description of Inadequate Acute Treatment 29 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 31 ' N D Patient's reported use of medication is not consistent. Parents do not appear to be very involved in management of the patient's asthma. Failed to take medication as prescribed. 40 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 41 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 42 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 45 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 48 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. 103 Table 24 Presence of Inadequate Acute Treatment of Patients with "Moderate-Persistent" Chronic Severity Patient Inadequate Treatment Description of Inadequate Acute Treatment 5 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 10 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 16 Y E S Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. 24 Y E S Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having p 2-agonist in the regimen. The patient did not receive any treatment for three days prior to hospital admission. 32 N D Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. Chi ld reports that the parents couldn't afford to purchase the corticosteroid medications. That is why they only had the salbutamol M D I at home. 36 Y E S Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having p 2-agonist in the regimen. The patient did not receive any treatment for three days prior to hospital admission. 38 N O N O ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. 104 Table 25 Presence of Inadequate Acute Treatment of Patients with "Non-Determinable" Chronic Severity Patient Inadequate Treatment Description of Inadequate Acute Treatment 18 YES Inhaled short-acting (32-agonist indicated for initial treatment but the patient did not report having p2-agonist in the regimen. 26 YES Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having P2-agonist in the regimen. The patient did not receive any treatment for two days prior to hospital admission. 28 YES Oral corticosteroids indicated for the severe exacerbation, but the patient did not receive oral corticosteroids in time. 37 YES Inhaled short-acting p2-agonist indicated for initial treatment but the patient did not report having P2-agonist in the regimen. The patient did not receive any treatment for two days prior to hospital admission. 43 N D N D 47 YES Oral corticosteroids indicated for the severe exacerbation, but the patient did not report having oral corticosteroids in the regimen. ND = Non-determinable; insufficient data to determine. Inadequate Treatment = The patient, patient of the patient did not report a dose indicated by the Guidelines in the regimen; or patient, parent, or physician reported noncompliance. 105 4.4 H E A L T H - R E L A T E D Q U A L I T Y O F L I F E The following sections describe results of the H R Q O L scores for the C A Q , P A Q L Q , and Q O L i F administered to patients and their parents during the hospital stay (Section 4.4.2) and six weeks after discharge from hospital (Section 4.4.3). 4.4.1 DESCRIPTION O F T H E STUDY S A M P L E The patients who participated in this component of the study were recruited from the sample of 61 children admitted to hospital for asthma or asthma-related symptoms as described in Section 3.1.1. In total, 35 of the 61 potential subjects participated in this component of the study. Others were not available during the admission, did not have time during the admission to respond to the questionnaires, or did not complete the questionnaires. O f the 35 patients who responded completely to one of the three H R Q O L instruments, 23 (66%) were male and 12 (34%) were female. Their mean age was 8.9 ± 3.3 years (median age, 8.6 years). The clinical status of this sub-group on admission was similar to the sample of patients who participated in the D R H A component of the study, as described in Section 4.1.2. The mean (± SD) body temperature of these patients on admission was 36.8 + 0.7 ° C . The mean respiratory rate was 32 ± 6 breaths per minute, the mean (± SD) heart rate was 127 ± 32 beats per minute, and the mean (± SD) oxygen saturation was 93.1 ± 106 3.2%. The first mean (± SD) P E F R , which was measured at hospital admission, was 64.8 ± 26.6% of the age and weight-adjusted predicted values. The second mean (± SD) P E F R , which was measured at hospital discharge or after being discharged, was 79.2 ± 36.4% of the age and weight-adjusted predicted values. 4.4.2 H R Q O L SCORES M E A S U R E D DURING T H E HOSPITAL STAY The C A Q , the P A Q L Q and the Q O L i F were administered to this study sample in accordance with the age criteria described in Table 2 of Section 3.2.3. 4.4.2.1 C A Q Fifteen o f 28 patients (54%) eligible by age were administered the C A Q - A . The domain scores for each of the 15 children administered the C A Q - A is shown in Table 26. The mean (± SD) score for the C A Q - A "Quality o f L i v i n g " domain was 31.1 ± 2 . 7 and the mean (± SD) score for the C A Q - A "Distress" domain was 11.3 ± 2.64. The "Quality of L i v i n g " domain has a range o f 10 (low Quality of L iv ing , very unhappy about all activities) to 40 (high Quality of Liv ing , very happy about all activities). The "Distress" domain has a range of 4 (low distress) to 15 (high distress). Fourteen of 18 patients (78%) eligible by age were administered the C A Q - B . The individual domain scores, mean scores, and summary statistics for each of the 14 children 107 Table 26 C A Q - A Scores Measu red D u r i n g The Hosp i t a l Stay Patient Quality of L iv ing Distress 3 32.7 12 13 28 12 21 25.8 12 23 36 14 26 31.5 12 29 32.6 13 35 32 14.5 38 28 11 39 32.7 7 40 30 10 48 34 6 52 28.8 10 53 33 8 54 31 14.7 56 30 13 Mean ± S D 31.1 ± 2 . 7 11.3 ± 2 . 6 Range of Scores 25 .8 -36 .0 6 .0 -14 .7 Possible Range 1 0 - 4 0 4 - 1 5 108 administered the C A Q - B are shown in Table 27. The mean scores for the "Active Quality of L iv ing , " and "Passive Quality of L i v i n g " domains were 28.3 and 17.4 respectively. The scores on the quality of living items increase with more enjoyment of the activities. The range for the "Active Quality of L i v i n g " domain, which measures physically active pastimes, is 7 (low Active Quality of Living) to 35 (high Active Quality of Living). The range for the "Passive Quality of L i v i n g " domain, which measures sedentary pastimes, is 4 (low Passive Quality of Living) to 20 (high Passive Quality of Living). The mean scores for the "Distress," and "Severity" domains were 15.9, and 15.1 respectively. The range for the "Distress" domain, which measures unhappiness about having asthma is 6 (low distress) to 30 (high distress). The range for the "Severity" domain, which measures severity of symptoms, is 6 (low) to 23 (high). Four of eight patients (50%) eligible by age were administered the C A Q - C . Each patient's domain scores, mean scores and summary statistics are shown in Table 28. The mean scores for the "Active Quality of L i v i n g " and "Teenage Quality of L i v i n g " domains were 20 and 11 respectively. Similar to the C A Q - B , the scores of the quality o f l iving items are greater with more enjoyment of activities. The range for the "Active Quality of L i v i n g " domain is 8 (low A Q O L ) to 36 (high A Q O L ) . The range for the "Teenage Quality of L i v i n g " domain, which measures the extent to which young people are engaged in social activities associated with the teenage years, is 5 (low sociability) to 23 (high sociability). 109 Table 27 C A Q - B Scores Measu red D u r i n g The H o s p i t a l Stay Patient Domain Active Quality of Liv ing Passive Quality of Liv ing Distress Severity 1 24.5 15 14 21 4 34 19 19 14 12 30 17 7 15 16 29 20 14 13 17 26 20 21 13 25 23 17 14 15 32 30 18 11 13 33 35 20 23.3 13 34 31 19 20 17 45 31 13 15 12 47 26.8 14 13 17 55 30.3 17 22.8 10 61 26 15 13 22 63 19.8 19 15 16 Mean ± SD 28.3 + 4.2 17.36 ± 2 . 3 15.86 ± 4 . 7 15.07 ± 3 . 3 Range of Scores 19 .8-35 .0 13 .0-20 .0 7 .0 -23 .3 10 .0-22 .0 Possible Range 7 - 3 5 4 - 2 0 6 - 3 0 6 - 2 3 110 Table 28 C A Q - C Scores Measured D u r i n g The Hosp i t a l Stay Patient Domain Distress Severity Reactivity Active Quality of L iv ing Teenage Quality of Liv ing 8 55 22 18 19 10 19 50 19 10 21 12 24 44.7 23 12 21 14 60 50 19 14 19 10 Mean ± SD 49.9 ± 4.2 20.8 ± 2 . 1 13.5 ± 3 . 4 20 ± 1.2 11.5 ± 1.9 Range of Scores 4 4 . 7 - 5 5 1 9 - 2 3 1 0 - 1 8 1 9 - 2 1 1 0 - 1 4 Possible Range 8 - 3 6 5 - 2 3 111 4.4.2.2 P A Q L Q Twenty of 29 patients (69%) eligible by age were administered the P A Q L Q . The mean age of the children was 10.8 ± 3 . 0 years. The scores for each domain for each patient are shown in Table 29 and the overall mean P A Q L Q score was 4.0 ± 1 . 3 . The range of scores of each domain of the P A Q L Q is one (maximum degree o f asthma-related symptoms and maximum limitation of activities and emotional function) to seven (no degree o f asthma-related symptoms and no limitation of activities and emotional function). Since the overall score is the mean score of each domain score, the overall H R Q O L score is one (poor H R Q O L score; maximum degree of asthma-related symptoms and maximum limitation of activities and emotional function) to seven (high H R Q O L score; no degree of asthma-related symptoms and no limitation of activities and emotional function). Nine of 29 parents of patients (31%) eligible by age were administered the P A C Q L Q . The mean score was 5.0 ± 1.4, as shown in Table 30. 4.4.2.3 Q O L i F Nineteen of 54 age-eligible patients and 19 parents/caregivers of children were administered the Q O L i F during the hospital stay. The mean (± SD) age of the children was 9.1 ± 3.3 years. The mean scores and standard deviations of the parents' and children's scores for each of the domains of the Q O L i F are shown in Table 31 and Table 32. The physical domain scores were calculated using the mean of the patients' top three 112 Table 29 P A Q L Q Scores Measu red D u r i n g the Hosp i t a l Stay Patient Domain Activity Limitations Symptoms Emotional Function Overall 1 4.4 5.4 4.5 4.8 4 4.2 3.9 3.8 4.0 5 2.1 2.5 2.7 2.4 8 3.7 3.9 2.6 3.4 17 3.7 6.1 3.7 4.5 19 2.9 3.0 3.5 3.2 24 4.2 3.3 3.2 3.6 25 2.8 3.4 2.5 2.9 26 4.1 6.8 5.4 5.4 29 1.4 2.4 1.5 1.8 32 2.9 2.7 3.3 3.0 33 6.4 6.8 6.0 6.4 34 4.6 4.2 4.1 4.3 45 4.6 5.5 5.0 5.0 47 3.0 3.0 2.9 3.0 52 7.0 7.0 6.7 6.9 55 3.6 5.6 5.2 4.8 60 3.7 3.6 2.3 3.2 61 4.5 4.7 2.6 4.0 63 4.0 4.7 3.6 4.1 Mean ± SD 3.9 ± 1.3 4.4+1.5 3.8 ± 1.4 4.0 ± 1.3 Range of Scores 1.4-7.0 2 . 4 - 7 . 0 1.5-6.7 1.8-6.9 Possible Range 1 - 7 1 - 7 1 - 7 1-7 113 Table 30 Parents ' P A C Q L Q Scores Measu red D u r i n g the H o s p i t a l Stay Patient Score 1 5.2 5 5.4 8 4.8 12 2.8 25 6.0 26 7.0 34 3.4 47 4.1 55 6.5 Mean ± S D 5.0 ± 1.4 Range of Scores 2 . 8 - 7 . 0 Possible Range 1-7 114 Table 31 Parents' Q O L i F Scores Administered During the Hospital Stay Patient ID Domain Physical Social Role Overall 1 7.0 6.8 6.8 6.9 8 4.3 6.0 5.2 5.2 12 4.3 3.6 5.5 4.5 17 7.0 6.6 5.7 6.4 25 6.7 6.0 6.3 6.3 33 6.3 6.7 6.5 6.5 34 6.0 4.3 4.0 4.8 38 5.3 3.5 3.0 3.9 40 N A 5.8 2.3 N A 45 6.3 6.3 6.6 6.4 46 3.3 3.5 2.0 2.9 47 N A 1.3 1.0 N A 48 4.3 6.6 5.7 5.5 52 7.0 7.0 7.0 7.0 53 3.7 4.2 1.0 3.0 55 6.0 7.0 7.0 6.7 60 2.5 4.3 5.0 3.9 61 5.5 6.4 5.0 5.6 63 3.6 3.0 1.3 2.6 Mean ± SD 5.2 ± 1.5 5.2+1.7 4.6 + 2.2 5.2+1.5 Range of Scores 2 . 5 - 7 . 0 1.3-7.0 1.0-7.0 2.9 - 7.0 Possible Range 1 - 7 1 - 7 1 - 7 1 - 7 NA = Data not available. Patient 40 did not indicate which three physical activities were most important. Patient 47 did not complete the QOLiF, although it was completed by the parent/caregiver. 115 Table 32 Children's Q O L i F Scores Measured During the Hospital Stay Patient ID Domain Physical Social Role Overall 1 5.0 4.0 2.0 3.7 5 3.0 1.3 1.8 2.0 8 5.7 5.0 5.8 5.5 17 7.0 7.0 7.0 7.0 24 4.7 6.5 6.0 5.7 25 2.7 1.5 2.3 2.2 26 6.3 3.3 1.0 3.5 29 4.7 6.0 2.0 4.2 33 6.7 7.0 7.0 6.9 34 6.0 6.3 6.1 6.1 38 5.0 5.5 6.5 5.7 40 N A 1.7 1.7 N A 46 4.0 2.8 3.0 3.3 47 N A N A N A N A 48 6.0 6.8 7.0 6.6 52 4.0 5.0 5.7 4.9 53 7.0 7.0 7.0 7.0 55 5.7 7.0 7.0 6.6 61 7.0 7.0 7.0 7.0 63 6.7 6.7 3.6 5.7 Mean ± SD 5.4+1.3 5.1 ± 2 . 1 4.7 ± 2 . 3 5.2 ± 1.7 Range of Scores 2 . 7 - 7 . 0 1.3-7.0 1.0-7.0 2 . 0 - 7 . 0 Possible Range 1 - 7 1 - 7 1 - 7 1-7 NA = Data not available. Patient 40 did not indicate which three physical activities were most important. Patient 47 did not complete the QOLiF, although it was completed by the parent/caregiver. 116 rated items. Data were missing for Patient 40 and Patient 47 because Patient 40 did not indicate which were his top three items, and Patient 47 did not complete the first administration of the Q O L i F . 4.4.3 C H A N G E IN H R Q O L SCORES M E A S U R E D SIX W E E K S A F T E R H O S P I T A L STAY Six weeks after the hospital stay, the H R Q O L instruments were re-administered to the patients available for follow-up to explore changes in measured H R Q O L in patients who were well enough to be active at home. 4.4.3.1 C A Q Only, four of the original 15 patients completed the second administration of the C A Q - A . The others were lost to follow-up. Changes in the C A Q scores are not reported because the sample size was inadequate and the results would not likely have been representative of the changes in the sample. 4.4.3.2 P A Q L Q Eleven of the 18 patients who were assessed with the P A Q L Q in hospital completed the second administration of the P A Q L Q . The mean age of this group was 11.6 ± 2.7 years. A s shown in Table 33, by six weeks after hospital admission, the overall P A Q L Q 117 H R Q O L score had increased from 3.8 ± 0.9 to 5.6 ± 1.3 (p = 0.0011), which represented a mean change in score of 1.8 points for overall H R Q O L . Consistent with a clinical improvement, the effect size for the overall P A Q L Q H R Q O L score was 1.5, indicating that the P A Q L Q was responsive to changes in patients' clinical status. The mean change in score for each of the domains were also similar; the mean change in each domain was 1.7, 1.6, and 1.9 for the activity domain, symptom domain, and emotional function domain, respectively. Effect sizes were similarly large for each of the domains of the P A Q L Q as shown in Table 33. Ten parents were administered the P A C Q L Q six weeks after hospital stay (Table 34). The mean score was 5.6 ± 1.3. The change in the mean score is not reported because only three of the nine parents who completed the first administration completed the second administration. The other parents were not available. With only three sets of matched scores, the change in mean score is not meaningful. 4.4.3.3 PATIENT-SPECIFIC A P P R O A C H T O H R Q O L A S S E S S M E N T : Q O L I F Only 10 children completed both the first and second administration of the Q O L i F . Two of the 12 children who completed the first administration were not available when the investigator met with parents for the follow-up meeting. Furthermore, one child did 118 Table 33 Children's P A Q L Q Scores Measured During Hospital Admission and Six Weeks After Hospital Stay Domain Patient Activity Symptoms Emotional Overall Limitations Function I H IC IH IC IH IC IH IC 1 4.4 6.0 5.4 5.9 4.5 5.9 4.8 5.9 5 2.1 6.1 2.5 6.8 2.7 6.7 2.4 6.5 8 3.7 5.9 3.9 6.4 2.6 6.2 3.4 6.2 17 3.7 3.4 6.1 4.6 3.7 3.8 4.5 3.9 19 2.9 4.2 3.0 6.5 3.5 6.6 3.2 5.8 25 2.8 4.4 3.4 4.7 2.5 4.7 2.9 4.6 34 4.6 6.6 4.2 6.5 4.1 6.3 4.3 6.5 45 4.6 6.4 5.5 6.5 5.0 6.7 5.0 6.5 47 3.0 2.5 3.0 3.1 2.9 3.2 3.0 2.9 55 3.6 6.7 5.6 6.7 5.2 6.9 4.8 6.8 60 3.7 6.3 3.6 6.2 2.3 5.9 3.2 6.1 Mean ± SD 3.6± 5.3± 4.2± 5.8± 3.6± 5.7± 3.8± 5.6+ 0.8 1.5 1.3 1.2 1.0 1.3 0.9 1.3 Paired t-test (2-tailed) p = 0.0015 p = 0.0084 p = 0.0003 p = 0.0011 Effect Size 2.2 1.4 2.1 1.5 IH = In Hospital IC = In Community Six Weeks After Hospital Stay 119 Table 34 P A C Q L Q Scores Measured 6 Weeks After the Hospital Stay Patient Score 5 3.2 8 4.6 17 6.3 19 3.9 29 6.3 34 7.0 45 6.7 47 5.2 52 6.2 55 6.2 Mean ± S D 5.6 ± 1.3 Range of Scores 3 . 2 - 7 . 0 Possible Range 1 - 7 120 not indicate which items were his three most important physical activities. The mean age of this group of 10 children was 9.0 ± 3.1 years. Eight of the 10 children were seven years of age or older. Table 36 show the summary results from the administration of the Q O L i F to these children during their hospital admissions and again six weeks later. Although mean scores increased with the corresponding improvement in the children's asthma,' none of the changes in domain scores reported by the children was statistically significant, as shown in Table 36. The effect sizes for the physical domain, social domain, role function domain, and overall scores were 0.4, 0.6, 0.3, and 0.3 respectively. Twelve parents completed the initial and follow-up administration of the Q O L i F . A s shown in Table 35, only the change in the parents' social domain scores was statistically significant. The effect sizes for the physical domain, social domain, role function domain, and overall score were 0.7, 0.5, 0.5, and 0.7 respectively. 4.4.3.4 RESPONSIVENESS O F T H E P A Q L Q A N D Q O L I F T O C H A N G E S IN PATIENTS' C L I N I C A L STATUS To explore the relative performance of the P A Q L Q and the Q O L i F , the changes in the physical domain scores o f the Q O L i F were compared to the changes in activity domain scores of the P A Q L Q (Table 37) among the six children who completed both instruments. The mean age of this subgroup of children was 11.2 ± 1.9 years. In this group, there was no significant change in either the parents' or the children's physical 121 domain scores of the Q O L i F . The parents' mean physical domain scores increased from 5.8 ± 1.0 to 6.1 ± 0.8 (p = 0.25). The children's mean physical domain scores increased from 5.0 ± 1.7 to 6.2 ± 0.5 (p = 0.11). However, the mean P A Q L Q scores of the children increased from 3.4 ± 0.9 to 5.5 ± 1.3 (p = 0.016). The effect size was much larger with the P A Q L Q than with the Q O L i F in these matched cases. 122 Table 35 Parents' QOLiF Scores Measured During Hospital Admission and 6 Weeks After Hospital Stay Domain Physical Social Role Overall I H IC IH IC IH IC I H IC 5 5.0 5.3 5.7 6.0 6.0 6.0 5.6 5.8 8 4.3 5.0 6.0 5.0 5.2 5.4 5.2 5.1 17 7.0 6.3 6.6 6.8 5.7 5.7 6.4 6.3 25 6.7 7.0 6.0 7.0 6.3 7.0 6.3 7.0 34 6.0 6.7 4.3 6.9 4.0 7.0 4.8 6.9 38 5.3 5.0 3.5 5.0 3.0 4.5 3.9 4.8 40 N A N A 5.8 6.8 2.3 5.8 N A N A 45 6.3 7.0 6.3 6.5 6.6 6.6 6.4 6.7 47 N A N A 1.3 1.7 1.0 1.3 N A N A 48 4.3 7.0 6.6 7.0 5.7 3.7 5.5 5.9 53 3.7 7.0 4.2 7.0 1.0 7.0 3.0 7.0 55 6.0 6.3 7.0 6.7 7.0 6.5 6.7 6.5 Mean ± SD 5.5 ± 1.1 6.3 ± 0.8 5.3 ± 1.7 6.0 ± 1.5 4.5 ± 2.2 5.5 ± 1.7 5.4 ± 1.2 6.2 ± 0.8 Paired t-test (2-tailed) p = 0.07 p = 0.037 p = 0.12 p = 0.78 Effect Size 0.7 0.5 0.5 0.7 I H = In Hospital IC = In Community Six Weeks After The Hospital Stay N A = Data Not Available. Patient 40 did not indicate which activities were most important to him. Patient 47 did not complete the Q O L i F , although it was completed by the parent/caregiver. Data that were not available were not included in the analysis. 123 Table 36 Children's Q O L i F Scores For the Physical, Role and Social Domain Measured During Hospital Stay and 6 Weeks After Hospital Stay Domain Physical Social Role Overall I H IC IH IC IH IC I H IC 5 3.0 6.3 1.8 6.0 1.3 6.3 2.0 6.2 8 5.7 6.3 5.8 6.2 5.0 7.0 5.5 6.5 17 7.0 7.0 7.0 6.0 7.0 7.0 7.0 6.7 25 2.7 5.7 2.3 5.7 1.5 6.0 2.2 5.8 34 6.0 5.7 6.1 7.0 6.3 6.9 6.1 6.5 38 5.0 4.3 6.5 5.5 5.5 5.5 5.7 5.1 40 N A N A 1.7 6.7 1.7 6.8 N A N A 48 6.0 7.0 7.0 4.7 6.8 6.2 6.6 6.0 53 7.0 4.7 7.0 4.3 7.0 4.2 7.0 4.4 55 5.7 6.3 7.0 6.5 7.0 6.9 6.6 6.6 Mean ± SD 5.3 ± 1.6 5.9 + 0.9 5.2 ± 2.3 5.9 + 0.9 4.9 ± 2.5 6.3 ± 0.9 5.4 ± 1.9 6.0 + 0.7 Paired t-test (2-tailed) p = 0.34 p = 0.14 p = 0.47 p = 0.45 Effect Size 0.4 0.6 0.3 0.3 IH = In Hospital IC = In Community N A = Data Not Available. Patient 40 did not indicate which activities were most important to them. Patient 47 did not complete the Q O L i F , although it was completed by the parent/caregiver. 124 Table 37 Comparison of Scores in the Physical Domain of the Q O L i F and Activity Domain Scores of the P A Q L Q in the Group of Six Children Who Completed Both the P A Q L Q and the Q O L i F Q O L i F Physical Domain Parents' Scores Q O L i F Physical Domain Children's Scores P A Q L Q Activi ty Domain Children's Scores Number I H ' IC IH IC IH IC 5 5.0 5.3 3.0 6.3 2.1 6.1 8< 4.3 5.0 5.7 6.3 3.7 5.9 17 7.0 6.3 7.0 7.0 3.7 3.4 25 6.7 7.0 2.7 5.7 2.8 4.4 34 6.0 6.7 6.0 5.7 4.6 6.6 55 6.0 6.3 5.7 6.3 3.6 6.7 Mean ± S D 5.8 ± 1.0 6.1 ± 0 . 8 5.0 ± 1.7 6.2 ± 0.5 3.4 ± 0 . 9 5.5 ± 1.3 Paired t-test (2-tailed) 0.25 0.11 0.016 ES 0.3 0.7 2.3 IH = In Hospital IC = In Community N A = Data Not Available. Patient 40 did not indicate which activities were most important to them. Patient 47 did not complete the Q O L i F , although it was completed by the parent/caregiver. 125 5. D I S C U S S I O N 5.1 T H E O V E R A L L S T U D Y S A M P L E Children who were five years or older with a diagnosis of asthma were included in the study. Children younger than five were excluded because much of the evidence supporting the recommendations of the N I H L B I guidelines have been based on studies in children five years of age and older. 3 2 A s noted in the guidelines, 3 2 the diagnosis of asthma is not as clear in children less than five years of age because the symptoms of asthma are similar to other respiratory conditions. 1 0 5 The respiratory symptoms typical of asthma, including wheezing, coughing, and breathlessness can be caused by respiratory tract infections, congenital anomalies, and mechanical or cardiogenic problems. For example, pneumonitis, cystic fibrosis, gastro-oesophageal reflux, wheezy brionchioli t is , 1 0 6 and other conditions may have similar clinical presentations in children. Without a firm diagnosis of asthma, it would have been difficult to determine the presence of a dose-related therapeutic failure, since the guidelines that were used to judge appropriateness o f patients' drug therapies applied only to those patients with a firm diagnosis of asthma. Thus, by including only those children five years of age or older, it was possible for the expert panel to judge which patients received inadequate treatment. A disadvantage of selecting only those children five years or older was that the number of eligible patients that were able to participate was reduced. A s can be seen in 126 Figure 2, the number of children admitted to hospital for asthma was inversely proportional to age. Ambulatory health care visits by children have been reported to vary inversely with age, especially for patients with asthma. 1 0 8" 1 0 9 The number o f children enrolled in the current study was highest in the month of September (Figure 1), and in general fewer children were admitted to hospital and enrolled in the study between December and February. Thereafter, the number increased through the spring season, between March and June. A similar seasonal pattern has been observed in a group o f 12,064 patients with asthma admitted to hospital between 1994 and 1995 in Quebec, Canada. 1 0 9 The increase in the number of hospital admissions in September may have been associated with the start of school year for the children. A t school, children are generally exposed to more infectious contacts. Respiratory tract infections are known to be triggers for exacerbations of a s thma 9 7 ' 1 1 0 and an association between the frequency of hospital admissions during the school period and the presence of respiratory tract infections has also been reported among children. 1 1 1 Similarly, the increase in the number of hospital admissions through the spring may have been associated with children's exposure to seasonal allergens, as it has been reported that seasonal allergens can trigger asthma exacerbations. 1 1 2" 1 1 3 The patients were acutely i l l on hospital admission according to their documented clinical status. A s described in Section 5.1.2, the patients' mean P E F R (where data were available) on admission was only 60.6% o f their predicted values. P E F R is correlated 127 with respiratory function and can generally be used to serve as an objective measure of lung function in the patient with asthma. 3 2 However, a number of factors make the P E F R readings difficult to interpret. 1 1 4 First, P E F R is very effort dependent, especially among young children. Proper technique and effort are required to obtain accurate and reproducible readings. Second, P E F R readings vary considerably among different brands of the device, and even among different units of the same model . 1 1 5 Third, population norms vary among Caucasians, Orientals, and B l a c k s . 1 1 6 In this study, although the investigator used the same P E F R model, the P E F R monitors varied among some patients who already owned a P E F R monitor. In future studies, supplying a standard P E F R monitor to patients and providing the same brand of P E F R monitor to each patient would help to reduce variability among different brands. However, with the same model P E F R readings can be inconsistent. 1 1 4 A better approach would be to measure F E V i rather than P E F R to provide the best objective measure o f lung function, however this is not practical for a large study in hospitalized children. A s shown in Table 16, the mean arterial oxygen saturation in room air on admission was only 93.3%, which is below the normal range (94-100% 1 1 7 ). Arterial oxygen saturation in room air is generally a good indicator of the severity o f exacerbation among patients with asthma. 1 1 8 The mean respiratory rate (Table 16) was 31.6 ± 7.3 breaths per minute, which was more than two standard deviations above the normal population mean. 128 Furthermore, all o f the patients' heart rates were higher than normal on admission to hospital. In addition, since patients were enrolled in the study, subsequent to being admitted to a hospitaf ward by a medical doctor, their inferred clinical status was poor. The majority of the patients was admitted to the Mount Saint Joseph Hospital site of The Children's and Women's Health Centre of British Columbia, which is the province's primary pediatric teaching hospital affiliated with the University of British Columbia. Thus, this study sample represented a group of children with respiratory symptoms of asthma severe enough to have required hospital admission. A n important feature of the study was the polarized change in health status of the study patients, as patients were admitted for acute exacerbations of asthma, and discharged in control o f their asthma symptoms. Thus, the patients' health status during their hospital admission was expected to be poor compared to when they were re-assessed, approximately six weeks after their hospital stay. B y prospectively evaluating this cohort of asthmatic patients in the community when their condition was improved it was possible to measure the patients' H R Q O L during their worst asthmatic state and compare it to their H R Q O L status when they were well in the community. 129 5.2 D R U G - R E L A T E D H O S P I T A L A D M I S S I O N S The results of this study indicated that a high proportion of the children admitted to hospital for asthma had a medication-related therapeutic failure associated with the hospital admission. Thirty-seven of 44 (84%) of patients' admissions that were evaluated by the panel of asthma experts were associated with a "definite" therapeutic failure and seven of 44 admissions (16%) were deemed to have been "possibly" drug-related (Figure 12). In all cases, the admissions were associated with therapeutic failures rather than adverse effects. However, i f the panel determined that symptoms of infection reported for the children provided sufficient evidence for a condition that could have explained the symptoms on admissions, then 23 of the 44 cases (53%, 95% CI = 36 - 67%) would have been considered "definite" and 21 of the 44 cases (48%, 95 % CI = 33 - 62%) would have been considered "possible" therapeutic failures. The estimated frequency of drug-related hospital admissions in this study is consistent with the research by Ordonez G A et al., 1 1 9 who examined the incidence of "preventable factors" associated with children three to 15 years of age admitted to hospital for acute asthma in Melbourne, Australia. Using a questionnaire, they interviewed 166 children to obtain data related to their hospital admissions. Although they did not use a standardized algorithm, the investigators reported that approximately 72% of the children had "between two and four preventable factors" associated with their hospital admission. They also reported that, although 44% of the patients had been 130 given an asthma crisis management plan, only 9% of these patients had followed their plan before admission. Other factors contributing to hospital admission included low levels of asthma knowledge (49%), inappropriate preventative treatment (31%), poor compliance with preventative treatment (21%), and failure to use prednisolone and overuse of pVagonists before seeking treatment. The investigators identified "preventable factors" related to the children's hospital admissions, but they did not evaluate the contribution of each factor to hospital admissions. 1 1 9 A s described in Section 2.1.3.2 few other studies have examined the frequency of drug-related hospital admissions in the pediatric patient population with asthma. Einarson et al. performed a meta-analysis of 36 studies that have examine drug-related hospital admissions in industrialized countries, primarily in North America and Europe. Their focus was on adverse drug reactions, defined as "any unintended of undesired consequence of drug therapy," and patient non-compliance leading to hospitalization. Non compliance was defined as deviation from a regimen written (and intended) by the prescriber and included undercompliance (i.e., taking too little) and overcompliance (i.e., exceeding prescribed dosage). They reported that the frequency of adverse drug reactions leading to hospital admission ranged from 0.2 to 21.7%, with a median of 4.9%. In a more recent meta-analysis, Roughhead et al.46 analyzed studies of drug-related hospital admissions in Australia. They reported that 2.4 to 3.6% o f all hospital admissions, 12% of al l admissions to medical wards, and 15 to 22% of all emergency admissions among the elderly were drug- related. Between 32 and 69% of drug-131 related admissions were preventable. Although the diagnoses implicated in the drug-related admissions were reported in some of the studies, the extent of drug-related admissions related to asthma was not established. Furthermore, non-compliance with medications was examined in only four of the 14 studies. It is l ikely that these previous estimates have been lower than that observed in the present study because of methodological differences and differences in the study populations. Only four studies in the meta-analysis by Roughhead et al.45 employed a set of objective criteria to assign a degree o f causality to each drug-related hospital admission. Furthermore, these previous studies did not specifically evaluate the population o f pediatric patients hospitalized for asthma. The present study is unique because it is the first one to have examined drug-related hospital admissions in pediatric patients with asthma using a set of objective criteria. 5.2.1 D R U G R E G I M E N O F PATIENTS IN T H E D R U G - R E L A T E D HOSPITAL ADMISSION C O H O R T Twenty-one o f 44 patients (48%) reported not taking any medication on a chronic basis for their asthma (Appendix 14). The most common type of "as-needed" medication reported by the patients or the parents for the chronic management o f asthma was salbutamol (Figure 9). Fourteen patients were taking only one regularly scheduled medication. The most common types of regularly scheduled medication reported by 132 patients or parents for the chronic management o f asthma were inhaled corticosteroids: budesonide and beclomethasone (Figure 7). However, only 32% of patients reported taking regularly scheduled preventative medication. This was lower than the frequency of preventive medication use reported by Ordonez G A et al.119 In their study of 266 children admitted to hospital for asthma, 42% had been using preventative treatment on a regular tjasis as prescribed by their physician. For the acute episode related to the hospital admission in the present study, 31 of the 44 patients (70%) took medications in addition to their "regularly-scheduled" chronic regimen. In 14 o f these 31 cases (45%), the children reported that they increased the dose of chronic medication and did not add additional drugs. One-third of patients did not report increasing the dose of their chronic medications or adding additional therapy for their acute exacerbation. In 25 of the 44 patients (57%), oral corticosteroids were required for the acute exacerbation (as described in Section 5.2.5), but only three (7%) of them took oral corticosteroids for the exacerbation related to the hospital admission. In the majority o f cases, the patient took salbutamol for the acute exacerbation (Figure 11). Ordonez G A et a/ . , 1 1 9 reported that 18% of children in their study with a previous diagnosis of asthma and an exacerbation lasting more than 24 hours did not take systemic corticosteroids prior to hospital admission, despite requiring bronchodilators more than every three hours. Ninety-five percent of patients failed to use an asthma crisis management plan. Among the 266 children studied, only seven (3%) took oral 133 corticosteroids prior to hospital admission for acute asthma. The investigators, however, did not classify patients according to severity of symptoms, and thus it was not possible to relate their findings to adherence to the guidelines. Future work would benefit from having objective evidence of patients' drug regimens. In the province of British Columbia, all prescriptions processed for each resident are recorded in the Pharmanet database. In the future, verification o f patients' medication histories with the Pharmanet database would provide more objective evidence of their drug therapy. A discussion of patients' chronic and acute drug therapy in relation to the N I H L B I guidelines is discussed in Section 5.2.5. 5.2.2 MODIFICATION O F H A L L A S ' A L G O R I T H M Although the set o f criteria has been applied by Hallas et al. in other studies2' 5 1 5 3 to evaluate drug-related hospital admissions, this is the first study to apply the approach to the population of pediatric patients admitted to hospital with asthma. In this population, it was necessary to adapt Hallas' approach with a modification related to the assessment of dose-related therapeutic failure (DTF) . 134 In Hallas' previous studies, a D T F was defined as an absence of therapeutic response that could be linked causally either to a prescribed dose that was too low, to drug non-compliance, recent dose reduction/discontinuation, interaction, or inadequate monitoring, as described in Section 2.1.3. Non-prescription of a drug was not considered to represent DTFs . The reason that Hallas has not considered lack of a therapeutic effect linked to non-prescribing is that for many conditions it is not clear what the best approach to treatment i s . 5 3 However, asthma is a specific condition for which the currently accepted approach to treatment has been generally accepted and made explicit in The National Institutes of Health (NIH) Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (1997) 3 2 and the Canadian Asthma Consensus Conference Summary of Recommendations?1, These guidelines clearly outline drug and non-drug treatment strategies for all patients with asthma five years of age and older that are supported by published scientific evidence. Furthermore, the recommendations in the asthma treatment guidelines that are related to the early use of corticosteroids are based on evidence suggesting that these drugs can reduce the severity of acute exacerbations of asthma 2 5" 2 9 , 1 2 0 - 1 2 8 and the need for hospital admissions. 2 8" 2 9 ' 1 2 7 " 1 2 8 Therefore, in the present study, non-prescription of a drug was included in the classification of dose-related therapeutic failures. A limitation of this modification to Hallas' algorithm is that validity of this algorithm with the modification w i l l require further study. Since there is no gold standard, future studies could compare the results of the modified algorithm to other 135 algorithms, or to decisions of a separate expert panel that assesses each drug-related hospital admission. 5.2.3 INTERPRETATION O F H A L L A S ' A L G O R I T H M IN R E L A T I O N T O RESPIRATORY T R A C T INFECTIONS Since respiratory tract infections are common in children with asthma, it was necessary to inform the expert panel about the interpretation of Criterion 5 of Hallas ' algorithm in relation to respiratory tract infections. In Hallas' algorithm, a "definite" causal relation is inferred only i f all five criteria (Table 9) are satisfied. To make the algorithm clearly applicable to the population of patients with asthma, the "condition" referred to in criterion five was interpreted to include evidence of a respiratory tract infection that could have explained the symptoms. The purpose of the explicit reference to respiratory tract infections was to reduce the chance that the expert panel would fail to consider a respiratory tract infection as a condition present that could explain the symptoms on hospital admission. The expert panel determined that in only six of the 44 admissions, a respiratory tract infection was a condition that could have explained the symptoms. In these six cases, the panel determined that there was only a "possible" causal relation between drug intake and dose-related therapeutic failure. Subsequent to the panel assessments, 14 additional cases 136 (Table 19) were noted in which some evidence of a respiratory tract infection was found. In these cases, the panel had apparently considered the evidence to be insufficient. If the panel had concluded that the evidence was sufficient in all cases, then it would have estimated that 23 (52%) of 44 of cases were "definite" dose-related therapeutic failures, and 21 (48%) of 44 of cases were "possible" dose-related therapeutic failures' Respiratory tract infections are common among children hospitalized for asthma. 1 1 1 ' 1 2 9 - 1 3 0 In this study some subjective or objective evidence o f an upper respiratory tract infection was reported in 25 (45.5%) of the 44 cases. In a recent study of 108 children admitted to hospital for acute exacerbations of their asthma, sensitive polymerase chain reaction assays, in combination with standard virologic techniques on patients' nasal aspirates, indicated that viral infections were associated with 80 to 85% of the observed asthma exacerbations. 9 7 In the study, "viruses were detected in 80% of reported episodes o f peak expiratory flow, 80% of reported episodes o f wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow." Similar results have also been reported with adults. 9 8 Thus, respiratory tract infections represent a common cofactor associated with children's symptoms leading to asthma related hospitalization. Since Hallas' algorithm takes this factor into account, an underestimation of the frequency of respiratory tract infections could markedly affect the results. 137 In the present study, it is possible that the frequency of upper respiratory tract infections was underestimated, because determination of the presence of upper respiratory tract infections was based only on patients' or parents' recall o f events and a review of the medical records. Had a more intensive method of data collection been used, then the estimated frequency of "definite" dose-related therapeutic failures might have been reduced. Some studies have shown that symptoms of asthma triggered by respiratory tract infections can be treated, reducing the need for hospi ta l izat ion. 1 2 5 ' 1 2 7 ' 1 3 1 - 1 3 3 For example, in the study by Brunette et a/ . , 1 3 1 that occurred between 1980 and 1984, "two groups of children in Montreal, Canada, with a mean age of 36.4 ± 3 . 9 months and 40.4 ± 4.9 months were monitored during a two-year period. Group 1, considered as the control group, received theophylline preparations and orciprenaline either on a continuous basis or during attacks. During severe attacks, albuterol (salbutamol) was administered by nebulization, with corticosteroids occasionally added for seven to 14 days in cases of poor response to albuterol. Group 2 received the same treatment during the first year. During the second year, however, a short-term course of oral prednisone (1 mg/kg) each day was given as soon as the first symptoms of an upper respiratory tract infection appeared, prior to any signs of wheezing. The results indicated that, whereas morbidity remained constant in the control group during the 2-year observation period, a significant decrease in the number of wheezing days (65%), attacks (56%), visits to the emergency room (61%), and hospitalizations (90%) occurred in group 2. A l l o f these results 138 were statistically significant. It was concluded that preschool children who suffer from repeated asthma attacks related to upper respiratory tract infections may benefit greatly from the preventive administration of corticosteroids." 1 3 1 However, a number of factors may make the results difficult to interpret. First, only 32 children participated in the study. With such a small sample size, it is difficult to generalize these results. Second, the patients in this study by Brunette et al. 1 3 1 were much younger than the patients in the current study. Since asthma is difficult to diagnose in very young children (as discussed in Section 5.1), improper diagnosis may have confounded the results. Finally, the patients and parents were not randomized or blinded to the treatment, and this could have confounded the results. In a double-blind randomized placebo-controlled crossover study, Svedmyr et al. reached similar conclusions using inhaled glucocorticoid therapy. 1 2 5 They investigated whether inhaled budesonide administered during the early phase o f U R T I , before asthma symptoms developed, could reduce or completely eliminate asthma symptoms in children with well-controlled asthma. The children were randomized in blocks of two, that is each child was treated with inhaled budesonide (Pulmicort Turbuhaler®) during one period and then received placebo during the next, or vice versa. Children were instructed to start treatment at the first sign of an U R T I , and to continue treatment for nine days. Sixty-seven treatment periods were completed. Eleven children visited the emergency room, but only three visits occurred during the budesonide therapy. A l l five children who required oral steroids and two patients who were admitted to hospital were in the 139 placebo group. Their results showed that inhaled budesonide could attenuate exacerbation of URTI-induced asthma in children. However, this was also a small study with only 26 children participating. Furthermore, inhaled budesonide was administered four times daily in this study. A less rigorous dosing regimen could affect the patients' responses, since it has been reported that four times daily dosing may have a better effect on sevefe asthma, or on the incidence of relapse than twice daily dosing. 1 3 4 In summary, respiratory tract infections appear to be commonly associated with asthma and can contribute to patients' asthma symptoms. Also , some studies have shown that the severity of exacerbations of asthma triggered by respiratory tract infection may be reduced with preventative m e d i c a t i o n s . 1 2 5 ' 1 2 7 ' 1 3 1 ' 1 3 3 ' 1 3 5 However, the evidence is not clear whether full compliance with proper preventative treatment is effective in all patients. Therefore, in the present study, it was necessary to include respiratory tract infections as a factor that could have contributed to asthma symptoms, in accordance to Hallas' algorithm. If it were true that full compliance with proper preventative treatment were effective in controlling the severity of symptoms of asthma triggered by respiratory tract infection in patients with asthma, then respiratory tract infections could be disregarded as a condition that could have explained the symptoms on admission accordance to criterion five of Hallas' algorithm. Unt i l further evidence is available, it w i l l be necessary to interpret respiratory tract infections as we have done in this study. Prospective 140 randomized controlled trials w i l l be required to examine the effectiveness of the N I H L B I guidelines on rates of hospital admissions in children whose asthma exacerbations are complicated by respiratory tract infections, in order to determine whether or not patients whose symptoms are triggered by respiratory tract infections and treated according to the recommendations of the N I H L B I guidelines can avoid the need for hospital admissions. 5.2.4 L A C K O F I N H A L E D AND O R A L CORTICOSTEROIDS R E P O R T E D IN T H E R E G I M E N For many cases in which the expert panel deemed there was a definite relation between drug intake and therapeutic failure, the patients appeared to have received inadequate preventative therapy with inhaled corticosteroids or inadequate treatment with oral corticosteroids during the acute episode. Some patients were inadequately treated chronically and during the acute exacerbation. The N I H L B I guidelines recommend that inhaled corticosteroids be used regularly in patients whose severity are classified as "mild persistent" or worse. Doubling the dose of regularly scheduled inhaled corticosteroids is also indicated in those patients who obtain a good response to short-acting pVagonist therapy during an acute exacerbation. Daily oral corticosteroids are indicated in patients with severe persistent asthma, and 141 in some patients with moderate persistent asthma. Oral corticosteroids are also indicated for patients who do not obtain a good response to short-acting pVagonist therapy during an acute exacerbation. For patients with a history of severe exacerbations with viral respiratory tract infections, oral corticosteroids are recommended at the first 32 sign of the infection. In the present study, 13 of the 16 patients (82%) who appeared to have chronic "mi ld persistent" asthma (Table 20) did not receive daily anti-inflammatory medication as indicated by the guidelines. Among the seven patients with chronic "moderate persistent" asthma (Table 21), none received anti-inflammatory medications every day. Five of the seven patients did not receive any doses at al l . The other two patients took their preventative medication sporadically, despite the guidelines recommendations that preventative medications be used every day in patients with moderate persistent asthma. In 25 of the 44 cases (57%), patients required oral corticosteroids based on the N I H L B I guidelines for the acute exacerbation but did not report the medication to be in their drug regimen. Patients reported taking oral corticosteroids in only three of the 25 cases, despite having symptoms severe enough to require hospital admission. Studies have provided evidence of the efficacy of corticosteroids in suppressing inflammation in asthmatic airways, inhibiting the inflammatory process, controlling asthma symptoms, 2 5 " 2 9 ' 1 2 0 " 1 2 8 improving lung funct ion, 2 5 " 2 9 ' 1 2 2 " 1 2 8 preventing 142 exace rba t ions , 2 8 - 2 9 ' 1 2 2 ' 1 2 8 ' 1 3 6 reducing hospital a d m i s s i o n s , 2 8 " 2 9 ' 1 2 2 ' 1 2 8 ' 1 3 6 and reducing asthma mortal i ty . 2 5 - 3 0 The data collected about patients' medication use were subjective, based on patients, parents, and physicians' reports. Although patients were asked to report all medication in their regimen, it is possible that some did not disclose all of their medication because they were not compliant with them. Since objective evidence about patients' actual drug use was not available, it is not possible to determine the extent to which inadequate treatment with inhaled or oral corticosteroids was related to non-compliance or lack of a prescription. A s well , one patient, (Patient 32), identified that the cost of medications was as a barrier to compliance. This was a surprising observation, considering that social programs are in place in the province of British Columbia, to help low income families purchase essential prescription medications, although it has been reported that asthma-related morbidity and mortality may be related to socioeconomic factors. 1 3 7 5.2.4.1 N O N - C O M P L I A N C E Compliance was assessed through an interview with each patient, as described in section 3.1.5. In this study, a patient was considered non-compliant with a medication i f the patient, parent, or healthcare provider reported that the individual was non-143 compliant with his or her medication. The degree of non-compliance reported by patients ranged from not taking regularly scheduled medication at all , to missing the occasional dose (Appendix 19). In many cases, the patients did not take any doses of prescribed preventative medication at all . More than half of the patients were considered to be non-compliant with their prescriptions. Poor compliance with preventative treatment has been identified as a factor related to hospital admissions in pediatric patients with asthma. 1 3 8 In fact, our estimate of the frequency of non-compliance in this study is relatively low compared to another study. 1 3 9 This may have been related to the method of data collection, rather than the fact the non-compliance was low in the study population. Since patients generally under-report non-compl iance , 4 3 , 1 4 0 - 1 4 1 the frequency of non-compliance is probably higher and would likely have been observed to be higher i f a more intensive monitoring scheme had been used. In future studies, a standardized method of evaluating compliance with preventative therapy could easily be incorporated into the patient interview with a four-item self reported adherence measure, which has shown concurrent and predictive va l id i ty . 1 4 2 A n assessment of compliance could also be performed by comparing patients' reported drug therapy with medications recorded in the provincial PharmaNet database, which records nearly all prescriptions processed for patients in the province of British Columbia. 144 5.2.4.2 L A C K O F A P R E S C R I P T I O N Patients may not have reported certain medications in their regimen because they had not been prescribed. However, based on the data collected, it was not possible to determine whether patients simply were not reporting medication because they did not have the medication prescribed, or whether they were actually prescribed the medication, but they did not use it. Future studies should record patients' health profiles through the provincial PharmaNet database to help determine which medications have been prescribed but not reported in their drug regimens. Furthermore, data collected from the family physicians' health records would help to determine which prescriptions were prescribed, but not filled at the pharmacy. 5.2.5 L A C K O F A D H E R E N C E T O E V I D E N C E - B A S E D GUIDELINES The N I H L B I guidelines make recommendations about the appropriate use o f preventative and acute drug therapy based on patients' chronic level of severity. The present study provided an opportunity to study the extent to which patients' chronic and acute asthma management were consistent with the recommendations of the N I H L B I guidelines. According to the stepwise approach for managing asthma in the N I H L B I guidelines, a patient's level of severity is based on symptoms and lung function 145 parameters. The N I H L B I guidelines recommend drug therapy based on a patient's level of severity. Thus, it was possible to examine the extent to which patients' drug therapies were consistent with the N I H L B I guidelines by comparing a patient's reported drug regimen with the drug therapy recommended by the N I H L B I guidelines. 5.2.5.1 M A N A G E M E N T O F C H R O N I C A S T H M A Patients were classified according to a level of severity from the clinical data that were collected from the interviews and from the medical charts. Thus, the accuracy of the classification of severity was dependent on the reliability of the data collected. Furthermore, the ability to determine inadequate chronic treatment was dependent on accurate classification of chronic asthma severity. In this study, classification o f severity was conservative, since cases that were questionable were placed in the less severe group. For cases in which it was not possible to categorize the patients' severity because data were insufficient, disease severity was classified as "non-determinable." A patient was considered to have had "inadequate treatment" of chronic asthma i f drug therapy indicated by the guidelines for the chronic treatment of asthma according to the patient's level of severity was not reported in the patient's drug regimen in the last three months; or i f the patient, parent, or physician reported that the indicated medication was in the regimen but that the patient was non-compliant in using it. Evidence of 146 inadequate treatment of chronic asthma was found in 19 of the 44 cases (43%). If the 6 patients in whom severity was "non-determinable" were excluded from the analysis, the frequency of inadequate chronic treatment would have been 58%). These results suggest that, despite the availability of the N I H L B I guidelines, physicians and patients are not managing asthma in a manner consistent with the guidelines. Only a few studies have examined the extent to which the N I H L B I guidelines have been adopted in North America. The most recent work was published by Halterman et al.,143 and Meng et al.144 Halterman et al. investigated whether children less than 16 years of age with asthma took maintenance medication according to the N I H L B I 32 guidelines. The study sample was recruited from respondents of the National Health and Nutrition Examination Survey, a large-scale national survey of 40,000 people conducted from 1988 through 1994. Patients who reported physician diagnosed asthma were contacted and interviewed. Patients were asked about the number of wheezing episodes, the number of acute health care visits for wheezing, the number of hospitalizations for wheezing during the past 12 months, and about medications used during the past month. Five hundred and twenty four children less than 16 years of age with moderate to severe asthma were identified in the study. Among these patients, only 26%) had taken maintenance medications in the previous month. Thus, 74% were inadequately treated according to the Guidelines. It is possible that their estimates of the frequency of inadequate treatment was higher than in the present study because they only 147 studied children with moderate to severe asthma, and they also included children less than five years of age. In a comparable study by Meng et al.,144 o f 6,703 patients 14 years and older, compliance with the N I H L B I guidelines was also consistently low. The patients in their study also had moderate to severe asthma using a classification scheme similar to those in the N I H L B I guidelines. The frequency of inadequate treatment with daily preventative medication as recommended by the guidelines, ranged from 49.5% to 61.0%. Poor compliance with the N I H L B I guidelines was consistent across all seven o f the geographical regions in the United States that were evaluated in the study. Furthermore, more than 10% of respondents in the study reported using a bronchodilator more than eight times daily. The primary limitation of this study was the low response rate to the questionnaire. The Health Survey for Asthma Patients, a 10-page, self-administered questionnaire was mailed in 1996 and 1997 to 35,515 members who were identified as having asthma according to the H M O ' s database. 11,647 members responded, but 3,150 respondents indicated that they did not have asthma. Excluding false positives and those patients with mi ld intermittent asthma, the final sample size was only 6,703 patients. The present study and previous studies 1 4 3" 1 4 4 have identified a discrepancy between patients' use o f long-term control medications and recommendations of the N I H L B I guidelines. These recommendations are supported by a large body of research that has provided evidence for the efficacy o f regularly scheduled inhaled 148 corticosteroids for symptoms, exacerbations, and incidence of hospital admissions. Although the retrospective studies suggest that patient adherence to the N I H L B I guidelines can have an impact on control of asthma symptoms, prospective randomized controlled studies are needed to determine whether or not the N I H L B I guidelines can provide measureable improvements for patients. 1 4 5" 1 4 6 5.2.5.2 M A N A G E M E N T O F A C U T E E P I S O D E Patients were also considered to have had "inadequate treatment" i f drug therapy indicated by the guidelines for treatment of the acute episode was not reported in the patient's drug regimen; or i f the patient, parent, or physician reported that the indicated medication was in the regimen but that the patient was non-compliant in using it. Evidence of inadequate treatment of the acute asthma episode was present in 39 of the 44 cases (89%), which is summarized in Table 22 to Table 25. A s reported in Section 4.3.2.2, many of the cases involved inadequate treatment with oral steroids during the acute attack, despite evidence that oral steroids given during an acute asthma attack can reduce symptoms 1 4 7 and the need for hospital admissions in patients with as thma. 1 2 8 ' 1 4 8 " 1 5 0 The most recent study by Horowitz et al., evaluated the effectiveness of oral 149 steroids in children with asthma using a prospective double-blind randomized placebo controlled design. Children who received a single dose of steroids, given orally in pediatric community clinics during an acute mild to moderate asthma attack, had reduced symptoms and did not require as many hospital admissions. Corticosteroids are known to suppress inflammation in asthmatic airways, improve lung function, control symptoms, reduce asthma mortality and the irreversible changes in airway function, and improve patients health-related quality of l i fe . 3 1 In some cases, the children's acute symptoms were also treated inappropriately with the use of oral antibiotics rather than oral steroids by their physicians. In the present study, two cases of drug-related therapeutic failure involved a general practitioner prescribing antibiotics for an acute asthma exacerbation prior to hospital admission. Furthermore, in both of these cases of acute asthma exacerbations, corticosteroids were not prescribed. This inappropriate practice has been reported by Jones et al. 1 5 1 who has investigated inappropriate management by general practitioners of acute asthma attacks associated with respiratory tract infections i n adults. 1 5 1 They reported that antibiotic prescription is a common practice by general practitioners when faced with an acute asthma attack associated with respiratory tract infection. Antibiotics are often prescribed for asthma attacks that are associated with respiratory tract infections, despite the fact that the respiratory tract infections that trigger asthma are mainly viral and antibiotic therapy provides no additional benefit in these cases . 1 5 2 - 1 5 4 150 5.2.6 UNDER-DIAGNOSIS O F A S T H M A Although patients without a prior diagnosis of asthma were excluded from the study, under-diagnosis may have contributed to some hospital admissions. One patient (Patient 14) was not formally diagnosed with asthma until she was admitted to hospital. She did have chronic symptoms of asthma for nearly six years prior to the hospital admission and had a chronic dry cough that was worse at night, since she was two years of age. The patient had also been wheezy at her general practitioner's office visits for almost three years and was finally diagnosed with asthma during the hospital admission. The second patient (Patient 9) had been seen by a general practitioner prior to her hospital admission, but a diagnosis of asthma was not made at the time. The general practitioner started the patient on amoxicill in, an antibiotic, earlier in the day of her admission. The patient developed increased respiratory difficulty and was admitted to hospital. These are two possible cases of under-diagnosis of asthma. Underdiagnosis of asthma, especially in female pediatric patients, is a phenomenon that has been reported in the literature. 1 5 5" 1 5 6 5.2.7 P R E V E N T I O N Using Hallas' algorithm to evaluate each case, all 44 drug-related hospital admissions evaluated by the expert panel were considered to be preventable. However, despite the evidence that medications can reduce symptoms and severity of exacerbations, it is not clear whether strict adherence to the N I H L B I guidelines can truly prevent 151 hospital admissions in all patients with asthma. To address this question, Mitchell et al examined risk factors for readmission to hospital in 1,034 children in Auckland, N e w Zealand. The medical records of patients discharged from hospital between 1986 and 1987 were examined for factors related to readmission to hospital. Factors that significantly increased readmission were female sex (relative risk (RR) 1.23; 95% confidence interval (CI) 1.03 to 1.46), young age (age < 5 years R R 1.71; 95% CI 1.41 to 2.08), number of previous admissions (one previous admission R R 1.32; two, R R 1.68; three, R R 2.00; four or more, R R 2.80), and inpatient intravenous treatment ( R R 1.29; 95% CI 1.08 to 1.55). They also reported that medical treatment and management did not influence readmissions. However, this statement was misleading. Besides the fact that the study was not randomized or controlled, the investigators did not actually evaluate drug therapy of patients before hospital admission. In their study, "the medical management of the asthma episode in the community could not be assessed because drug treatment before admission to hospital was poorly recorded." 5 7 The investigators actually examined the "intention to treat," based on whether or not the association between patients having prophylactic therapy prescribed on discharge from a previous hospital admission was a factor associated with future hospital readmissions. They did not determine whether prescriptions for preventative medications were filled or taken. Considering the high rate of non-compliance with preventative medications in this study, it is not surprising that the investigators did not find an association between prescribed preventative medications and hospital 152 readmissions using an "intention to treat" analysis. Again, using an "intention to treat" analysis, they also examined the association between patients having an action plan on discharge from a previous hospital admission and future hospital readmissions. The investigators reported that "the use of action plans" did not predict readmissions. The most likely explanation for this is that since this was an "intention to treat" analysis, the authors'did not actually evaluate patients' use of an action plan. Therefore, it was not surprising that they did not find an association. In an earlier study, Mitchell et al151 reported that patients followed by an asthma nurse educator actually had an increased frequency of emergency hospital visits compared to those children in a controlled group. This was a randomized controlled study of 360 children aged two to 14 years of age. Every month, a nurse performed a follow-up evaluation with the treatment group. After six months, inhaled corticosteroid use was 34.9% in the treated group compared to 21.0 % in the control group. However, patients in the treated group used hospital services for severe attacks of asthma more than control patients (34.2 vs. 10.5%). A possible explanation for this unexpected result is that the action plan at the time of the study instructed patients to call an ambulance or to seek urgent medical attention i f the relief of their bronchodilator was short-lived, or they had difficulty with speaking or were cyanosed. This particular instruction may have shifted the medical care from the community to the hospital. A more recent study by Mayo et al.158 reported opposite results in an adult 153 population with asthma. The investigator prospectively randomized 104 adult patients with asthma to treatment and control groups. Patients in the treatment group were taught aggressive self-management strategies in case of marked asthma exacerbation. Patients in the control group received their regular outpatient care. Patients who were in the treated group had a threefold reduction in readmissions and a two-fold reduction in hospital days compared to patients in the control group. Thus, this study showed that improving self management can reduce the incidence of hospital readmissions. Barnes has reviewed the evidence for the clinical efficacy o f corticosteroids in asthma. Studies have shown that corticosteroid therapy is efficacious at reducing asthma symptoms. 1 2 2 " 1 2 3 Studies have also shown that they are efficacious in chi ldren. 1 5 9 " 1 6 0 However, it is not known whether corticosteroids can reduce the incidence o f hospital admissions, or whether strict adherence to asthma treatment guidelines that recommend the use of corticosteroids can prevent hospital admissions in patients who are fully compliant. Some retrospective, cross-sectional studies have suggested that hospital admissions can be prevented. 2 8" 2 9 ' 1 2 2 ' 1 2 8 , 1 3 6 To address this question, prospective, randomized, controlled trials w i l l be required. Two major problems make it difficult to properly design randomized controlled trials to answer these questions. First, since the incidence of hospital admission is relatively rare, a very large sample size would be required. Second is the problem of confounding by severity. Generally, inhaled corticosteroids are more likely to be 154 prescribed for patients who have more severe symptoms. These patients in turn may be at a higher risk of hospital admission. Thus, patients in retrospective studies who are taking inhaled corticosteroids could actually have more hospital admissions than patients who are not treated with inhaled corticosteroids. Despite these challenges, it is clear that more studies w i l l be needed to determine whether full compliance with the N I H L B I guidelines can reduce hospital admissions and the utilization of other healthcare resources. 155 5.3 H E A L T H - R E L A T E D Q U A L I T Y O F L I F E A s discussed in Section 2.2, H R Q O L in children with asthma needs to be investigated because asthma is a disease with highly variable symptoms and the effect of the disease on patients lives and their H R Q O L is complicated by their social, emotional, and physical needs. 7 5 ' 1 6 1 B y simply capturing physiological parameters, clinicians would not be able to assess the full impact of the disease on patients without measuring their H R Q O L . H R Q O L instruments can complement conventional measures o f physical function (e.g., F V C , F E V i and other lung function parameters) in children with asthma to provide a more comprehensive measure of disease impairment. Furthermore, since parents' reports of their children's H R Q O L may not be accurate, direct measures of children's H R Q O L from a child's own perspective are needed. Currently, the most developed tools to measure H R Q O L from a child's perspective include the C A Q and P A Q L Q . For these instruments to be useful in determining the effect of change in clinical status for children with asthma, validity, reliability, and responsiveness must be evaluated. So far, only some psychometric properties of these instruments have been tested. The present study provides further evidence o f the validity and responsiveness of the P A Q L Q and examines the utility o f a patient-specific approach to H R Q O L assessment. 5.3.1 T H E STUDY S A M P L E The patients who participated in this component of the study were recruited from 156 the sample of patients who participated in the first component of the study. Thus, these patients were acutely i l l during their hospital stay, as discussed in section 5.1. Six weeks after hospital stay, all the patients had already been discharged and were living in the community, thus it was possible to measure these same patients' H R Q O L when their condition had improved. In total, 35 of the 61 potential subjects participated in this component of the study. Others were not available during the admission or did not have time during the admission to respond to the questionnaires. These patients were excluded from the analysis. 5.3.2 H R Q O L M E A S U R E D D U R I N G H O S P I T A L S T A Y A sufficient number o f patients completed the C A Q - A and the C A Q - B to provide profiles of H R Q O L scores of children with acute asthma symptoms. The C A Q - A has previously been administered to four study samples. French et al.162 have reported that C A Q - A Quality of L iv ing domain scores do not correlate with disease severity. This study provides further evidence that this may be true. The mean Quality of L iv ing domain score of 15 children who completed the questionnaire in the current study was 31.07 ± 2.67 and the range of possible scores in this domain is 10 (low Quality of Living) to 40 (high Quality of Living) . This mean 157 score was similar to the other scores previously reported, although severity differed among the groups. French et al" previously reported that the DIS domain scores appeared to correlate with disease severity. Although the sample size in the present study was too small to compare the Distress domain scores o f patients with less severe asthma with the Distress domain scores of patients with more severe asthma, it has been postulated that the generic questions within the C A Q - A may make the instrument less responsive to differences in patients' clinical asthma severity. These generic items may have less discriminative and/or evaluative properties than disease-specific items for two reasons. First, as discussed by Rutishauser et al., the way the generic items are framed in the instrument may not help to focus the children's perception about the importance of asthma symptoms on their H R Q O L . For example, generic items in the instrument ask children to evaluate activities without instructing them to interpret the items in relation to their health status. These activities may or may not have been performed by the patient. Since children are not instructed to interpret the activities in relation to their health status, their answers are more likely to have been influenced by personal preference than the status of their disease. Second, some of the items themselves are not expected to be affected by asthma severity. For example, the C A Q includes items related to children's reading books. Since reading books is a physical activity that is not expected to be influenced much by asthma, these items may help explain the instrument's lack of discriminative and evaluative properties. Another explanation is that children's 158 actual H R Q O L may correlate poorly with their clinical status of asthma. However, many instruments have been shown to be responsive to changes in patients. It is also possible that children's H R Q O L improves during a hospital admission compared to when they are in the community because parents and healthcare providers may provide more attention to them. Therefore, it would be difficult to measure a subsequent improvement in patients' H R Q O L after they are discharged because their baseline H R Q O L would have already improved when they were in the hospital. Methods of assessment and procedural differences could also have confounded the results. In the study be French et al.,99 the administration of the questionnaires were not supervised by the investigators. In the present study, the patients were observed during the administration, and the investigator was present to answer any questions about the questionnaires. However, it is not known what effect the presence or absence of a parent or the investigator could have on the children's reported H R Q O L . More studies w i l l be needed to examine the effect of parents or investigators on children's H R Q O L scores. In the present study, 14 children who were between eight and 11 years of age completed the C A Q - B . The C A Q - B scores for the Active Quality of L iv ing domain and the Passive Quality of L iv ing domain of patients in the present study (Table 27) were also similar to the scores that have been previously reported." The Active Quality of L iv ing score and the Passive Quality o f L iv ing domain score in the present study were 28.3 ± 4.2 (median = 29.5) and 17.4 ± 2.3 (median - 17.5) respectively. These scores were similar to the other median scores previously reported, even though the patients in the 159 present study were patients with more severe asthma symptoms. It appears from these data that these domains do not correlate well with patients' severity o f asthma symptoms and that these domains do not have good discriminative properties. A possible reason that the Active Quality of L iv ing and the Passive Quality of L iv ing domains correlate poorly with asthma severity is that the items in the C A Q - B do not ask children to answer questions in relation to any particular time frame. For example, one of the items in the Active Quality of L iv ing domain of the C A Q - B is "Which picture describes how you feel when you play games outside (like ball games) with your class?" Since the child is not instructed to answer the question in relation to a particular time frame, the item could be assessing children's enjoyment of these activities, rather than the impact of asthma symptoms on their enjoyment of these activities. A n unexpected observation was reported in Distress and Severity domain scores. In the present study, the Distress domain score was only 15.9 ± 4.7 whereas in previous studies" the Distress domain score has been in the range of 23 to 25 among patients with mi ld to severe symptoms. The Distress domain is designed to measure feelings about asthma symptoms. It was expected that the children in this study with more severe symptoms would report more Distress and have a higher Distress domain score than patients with less mild symptoms. However, patients in this study actually reported less Distress than patients in the previous studies with less severe asthma symptoms. 160 Although changes in P A Q L Q scores have been previously reported, actual P A Q L Q scores have not yet been reported in the literature. This is the first study to report P A Q L Q scores of children with symptoms of asthma severe enough to require hospital admission. The mean score and the individual domain scores were in the middle of the range, which is 1 (low) to 7 (high), for the P A Q L Q . A s shown in Table 29, the mean P A Q L Q score o f the children in the current study with severe asthma symptoms in hospital was 4.0 ± 1.3, and the individual mean domain scores ranged from 3.9 to 4.4. Standard deviations of individual domains also ranged from 1.3 to 1.5. The children's " Q O L i F " scores measured when the children were acutely i l l in hospital are shown in Table 31 and Table 32. With this level of severity, the children's and the parent's mean scores were 5.2 ± 1 . 7 and 5.2 ± 1 . 5 respectively. The mean scores were already at the higher end of the range, which was 1 (low H R Q O L ) to 7 (better H R Q O L ) . Although both instruments use a 7-point likert scale for responses to each item, the primary difference between the " Q O L i F " and the P A Q L Q are that the " Q O L i F " incorporates a graphic image with each response choice. It is possible that these graphic images may be interpreted differently compared to the textual response items of the P A Q L Q . These differences in interpretation could potentially have skewed the children's responses to the higher end of the scale. The variability observed in the " Q O L i F " scores were also slightly higher 161 than that observed with the P A Q L Q , despite having the same range of possible scores. Again, i f the graphical images are less accurate descriptive response items compared to textual descriptions, it is possible that they may have contributed to the increased variance observed in the responses to the " Q O L i F . " Further studies w i l l need to be done to evaluate the precision of textual descriptions compared to graphical descriptions of response items in H R Q O L questionnaires. 5.3.3 C H A N G E IN H R Q O L SIX W E E K S A F T E R HOSPITAL STAY It was initially intended that the responsiveness of the C A Q would be investigated. However, with such a small sample of patients, it was not possible to examine the responsiveness of the C A Q to changes in patients' clinical status. Further studies w i l l be needed to examine the evaluative properties of this instrument. Since the C A Q has a component for each age sub-group, a sufficient number of patients for each age subgroup w i l l be required. The P A Q L Q scores improved six weeks after hospital discharge compared to scores reported when children were in the hospital. These results (shown in Table 33) are consistent with other studies that have reported that health related quality of life instruments can be sensitive to changes in patients' clinical status. 8 9 This is the first study to report the effect size of the change in the overall 162 P A Q L Q score and for each of the domains for a group of children who were acutely i l l in the hospital and whose clinical condition improved enough for them to be in the community. The effect size for overall H R Q O L in these patients was 1.5. The effect sizes for the symptom domain, activities domain, and the emotional function domain were 1.4, 2.2, and 2.1, respectively. Juniper et a/. . 8 0 have previously reported Guyatt's Index of Responsiveness 9 3 for the P A Q L Q . Guyatt's Index of Responsiveness is calculated by taking the ratio of the minimal clinically important difference (MCID) to the variability in stable subjects, which is the square root of two times the mean square error of scores in stable subjects.9 3 The M C I D is defined as the "smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence o f troublesome side effects and excessive costs, a change in the patient's management."1 It is estimated by taking the mean change in score for each domain of an instrument where patients had a Global Rating o f Change 1 score o f 1 to 3. In the study (described in 2.2.5.1), the P A Q L Q , the Feeling Thermometer, and a clinical asthma control questionnaire were administered to the children after 1 week, 5 weeks, and 9 weeks. Guyatt's Index of Responsiveness was calculated for the children whose asthma was classified as changed. The index of responsiveness based on the minimal clinically important difference (MCID) and the pooled within subject standard deviation of all patients in the study was 0.59. Although Juniper et a / . 8 0 did not report effect sizes, they reported that the mean change in scores for children whose condition changed were 0.79, 0.90, 0.81, 163 and 0.70 for the overall H R Q O L , activity domain, symptom domain, and emotion domain, respectively. In the current study, the mean changes in scores were 1.8, 1.7, 1.6, and 1.9 for overall H R Q O L , the activity domain, symptom domain, emotional domain, respectively. The mean changes in scores for overall H R Q O L and for the domains were larger in the present study compared to the changes reported in the study be Juniper et al.80 The larger change was expected because the clinical change experienced by patients in the current study was larger than the clinical change experienced by patients in the study by Juniper on et al. In the current study, all patients who participated were considered to have had severe asthma initially and all experienced a similar clinical improvement. The children's asthma status generally changed from being very severe (hospitalized) to well (discharged from hospital). On the other hand, in the study by Juniper et al. the sample population had a range o f asthma severity at the start of the study. The degree of clinical change was not as large as the one in the current study because children were not treated in the same manner. Furthermore, in Juniper's study, children whose condition only changed moderately were included. Thus it was expected that a larger change in score would be observed in the present study. These results provide evidence that the P A Q L Q is responsive among patients with severe asthma and that it is an instrument that appears to be responsive to large changes in asthma severity. Although the current study did not report the M C I D , the M C I D ' s for each 164 domain of the P A Q L Q and for the overall P A Q L Q has already been reported by Juniper et a/ . 8 0 They are 0.42, 0.70, 0.54, and 0.28 for the overall H R Q O L , the activity domain, symptom domain, emotional domain, respectively. Thus, all o f the changes in the present study can be considered to be clinically significant, i f we assume that the M C I D was properly estimated by Juniper et al. However, it is possible that Juniper et al. may have inaccurately estimated the M C I D and thus obtained an inaccurate estimate of the index of responsiveness using Guyatt's method. In order to calculate the M C I D , it was necessary to compare the children's scores with their Global Rating of Change score. However, since there was low agreement about which patients actually improved or stayed the same then the index of responsiveness based on Guyatt's method may also have been inaccurate. The current study is important because it provides an additional measure of instrument responsiveness for the P A Q L Q . It was also observed that variability in children's mean overall P A Q L Q scores and P A Q L Q scores in each domain increased after hospital discharge, as shown in Table 33. The increased variability observed in the P A Q L Q scores after hospital discharge may have represented variability in the children's degree of clinical improvement after being discharged from the hospital. During hospital admission, children were considered to have had severe asthma symptoms and were considered to have been in their worst asthmatic state. Furthermore, the children's daily activities and environments were all very similar in the hospital environment. However, after being discharged, the children returned to their homes, where their environments were not similar. Their 165 degree of clinical improvement may also have varied. Some children may have had mild intermittent, mild persistent, or moderate asthma in the community. These effect sizes observed in the P A Q L Q scores were also much larger than the effect sizes observed with the " Q O L i F . " The " Q O L i F " was investigated as an interactive approach to H R Q O L assessment using individualized items to improve the responsiveness of the instrument. However, in the present study, overall instrument scores, and scores of each domain of the Q O L i F did not appear to be as responsive as the P A Q L Q individual domains or to the overall H R Q O L P A Q L Q scores to changes in patients' clinical asthma severity. A possible explanation for the lack of responsiveness exhibited by the Q O L i F is that it had a variable number of items. Without a limit to the number of items that a patient could identify as important to him or her, a patient could potentially identify a few relevant items, and a large number of weakly relevant items. Since item domain scores are equally weighted, a large number of weakly relevant items could attenuate a large change in score among the more relevant items. However, even the three most important physical domain items o f the Q O L i F among a group o f matched patients did not seem to be as responsive as the five Activi ty domain items of the P A Q L Q . This was not expected since the five Activi ty domain items of the P A Q L Q are very similar to the items of the Q O L i F . In fact, the first three individualized items of the P A Q L Q are similar to the physical domain items o f the Q O L i F . The first three individualized items o f the P A Q L Q ask the patient to rate how much they have been bothered by asthma in performing each of three patient-identified items. The main 166 difference between the P A Q L Q Activity domain and the Q O L i F physical domain is the addition of 2 items in the P A Q L Q . One item asks the child to rate how often asthma makes him or her feel angry. The other item asks the child to think about all the activities that he or she did in the last week, and to rate how much he or she had been bothered by asthma doing these activities. The addition of these two items may account for the increased responsiveness of the P A Q L Q compared to the Q O L i F . These data suggest that the approach to H R Q O L assessment using a large number of individualized items may not improve the responsiveness of questionnaires. It appears that the P A Q L Q was more responsive than the Q O L i F at measuring changes in H R Q O L in children. Another explanation is that children's H R Q O L in the current study actually did not change as much as the P A Q L Q suggested. Rutishauser et a / . 1 6 3 has commented that the P A Q L Q ' s focus on emotional well-being and symptoms may contribute to the instrument's good responsiveness, but its lack of a social domain as well as other psychosocial issues undermines the validity of the instrument. Perhaps i f the instrument included more items related to these issues, it would not be as responsive as it seems. Further studies w i l l be required to provide more evidence of the validity of the P A Q L Q to measure H R Q O L in pediatric patients with asthma. 167 6. C O N C L U S I O N S Using a standard set of objective criteria for the evaluation of drug-related hospital admissions and an expert panel trained in the therapeutic management of asthma, this study has found that 84% of pediatric patients admitted to hospital for asthma or asthma-related symptoms were drug-related. However, 45.5% of these cases were also associated with some evidence o f a respiratory tract infection, which could also have explained the symptoms. Most children admitted to hospital typically were inadequately treated prior to their hospital admissions according to the National Institutes of Health (NIH) National Heart Lung and Blood Institute Expert Panel Report II Guidelines. The majority of cases involved inadequate use of long-term control medications, and inappropriate management of acute exacerbations. For example, 82% of patients who had "mi ld persistent" asthma did not report receiving daily anti-inflammatory therapy, and only three o f 25 patients who had evidence o f requiring oral corticosteroids reported taking them prior to being admitted to hospital. Furthermore, it was found that these drug-related admissions were deemed to be preventable. In the future, prospective randomized placebo controlled trials using more objective evidence about patients drug therapies may provide further evidence o f the effectiveness of strict adherence to international guidelines on the incidence o f hospital admissions in children with asthma. In future studies, drug therapies should be verified through the use o f objective prescription databases. 168 The responsiveness of the P A Q L Q and a more patient-specific approach to H R Q O L assessment have been reported. The P A Q L Q was responsive to the changes in clinical status that patients with asthma experienced when they were hospitalized as compared to when they were not hospitalized. However, the patient-specific approach to H R Q O L assessment did not appear to improve the responsiveness of a questionnaire. 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O P • • • X o tu c o ra E O s c j r w> O o XJ XJ ra O X X J rt JD o o o Z "r t X J j D rt " t > 3 a c o a> c X) O -r> x rt-2 * g -5 .y 3 ^ O ~ -c O Cl E I I X rt 01 fr 0» > tu «-» 3 o rt <-> rt rt E j r rt 0> rt o -fr s £ £ o -S M c t-OJ rt a) 5 O) to § = fr « rt w QJ Si " O tu Q a l 0 0 o 215 A p p e n d i x 4 P A Q L Q PAEDIATRIC ASTHMA QUALITY OF LIFE QUESTIONNAIRE INTERVIEWER ADMINISTERED McMASTER UNIVERSITY HAMILTON, ONTARIO CANADA For further information: Elizabeth Juniper, MCSP, MSc Associate Professor Department of Clinical Epidemiology and Biostatistics McMaster University Medical Centre, Room 2C11 1200 Main Street West Hamilton, Ontario, Canada L8N 3Z5 Telephone: (905)525-9140 x 22153 Fax: (905)577-0017 E-mail: Juniper@ms.mcmaster.ca CAJUNIPERVQUESTION^AED.irsT F E B R U A R Y 1 9 9 5 PAEDIATRIC ASTHMA QUALITY OF LIFE QUESTIONNAIRE THE PAEDIATRIC ASTHMA QUALITY OF LIFE QUESTIONNAIRE HAS BEEN TESTED AND VAUDATED USING THE WORDING AND FORMAT THAT FOLLOWS. IT IS IMPORTANT THAT INTERVIEWERS ADHERE TO THE EXACT WORDING WHEN ADDRESSING THE PATIENT (REGULAR TYPE) AND FOLLOW THE INSTRUCTIONS (ITALIC TYPE). DEVIATION FROM BOTH WORDING AND INSTRUCTIONS MAY IMPAIR THE RELIABILITY AND VALIDITY OF THE QUESTIONNAIRE. I want you to tell me all the things you do in which you are bothered by your asthma. CIRCLE THE NUMBER ON THE ANSWER SHEET UST ADJACENT TO EACH ACTIVITY MENTIONED. F AN ACTIVITY MENTIONED IS NOT ON THE UST, WRITE IT 94, 94 THE RESPONDENTS OWN WORDS, IN THE SPACE PROVIDED. Together, we are going to look at a list of things that you may have done during the last week. Because of your asthma, you may have found some of these activities difficult to do or not very much fun. Let's look at the list and you tell me in which activities you've been bothered by your asthma during the past week. If you haven't done something on the list or if it hasn't bothered you, just say "no". READ ACnVTTBES, OMITT84G THOSE WHICH RESPONDENT HAS DENTFED SPONTANEOUSLY. PAUSE AFTER EACH ACTIVITY TO GIVE THE PATIENT A CHANCE TO REPLY. CROSS OUT THE ACTIVITIES WHICH THE PATIENT INDICATES ARE NOT TROUBLESOME USING A THICK DARK FELT PEN. Can you think of any other activities in which you are bothered because of your asthma? Of the activities listed, I want you to tell 2 ] 8 tiich ones bother you the most 2 TURN THE ACTIVITY SHEET TO PATENT. TOGETHER, READ THROUGH ALL THE IDENTIFIED ITEMS. Which of these activities bothers you the most? WRITE ACTIVITY ON BOTH THE QUESTIONNAIRE AND THE RESPONSE SHEET. _ Of the remaining activities, which one bothers you the most? RECORD RESPONDENTS ANSWERS AND CONTINUE UNTIL 3 ACTIVITIES HAVE BEEN BDENIIHLD. SHOW THE BLUE AND GREEN CARDS TO THE PATIENT AND EXPLAIN THE SCALES. RECORD THE PATENTS ANSWERS ON THE RESPONSE SHEET. I now want you to tell me how much you were bothered by your asthma while doing these activities. I will tell you which card to use. Pick the number which best describes how much you were bothered by your asthma in doing each activity during the last week. How much have you been bothered by your asthma in (ACTIVITY 1: ) during the past week. [BLUE CARD] How much have you been bothered by your asthma in (ACTIVITY 2: ) during the past week. [BLUE CARD] How much have you been bothered by your asthma in (ACTIVITY 3: ) during the past week. [BLUE CARD] How much did COUGHING bother yc? 1 9 . he past week? [BLUE CARD] A 1. A 2. A 3. s 4. 3 E 5. H o w often d id your as thma make y o u fee l F R U S T R A T E D dur ing the pas t w e e k ? [ G R E E N C A R D ] s 6 . H o w often d id your as thma m a k e y o u fee l T I R E D dur ing the pas t w e e k ? [ G R E E N C A R D ] E 7. How often did you feel W O R R I E D , C O N C E R N E D , O R T R O U B L E D because of your asthma dur ing the past w e e k ? [ G R E E N C A R D ] s 8. How-much d id A S T H M A A T T A C K S bother you dur ing the pas t w e e k ? [ B L U E C A R D ] E 9. H o w often did your asthma make y o u fee l A N G R Y dur ing the pas t w e e k ? [ G R E E N C A R D ] s 10. H o w much d id W H E E Z I N G bother you dur ing the pas t w e e k ? [ B L U E C A R D ] E 11 . H o w often d id your as thma make y o u fee l I R R I T A B L E dur ing the pas t w e e k ? [ G R E E N C A R D ] s 12. H o w much d id T I G H T N E S S IN Y O U R C H E S T bother y o u dur ing the pas t w e e k ? [ B L U E r~- C A R D ] E 13 . H o w often d id you fee l D I F F E R E N T O R L E F T O U T b e c a u s e of your as thma dur ing the past w e e k ? [ G R E E N C A R D ] s 14. H o w much d id S H O R T N E S S O F B R E A T H bother y o u dur ing the past w e e k ? [ B L U E C A R D ] E 15. H o w of ten d id y o u f e e l F R U S T R A T E D B E C A U S E Y O U C O U L D N T K E E P U P W I T H O T H E R S dur ing the pas t w e e k ? [ G R E E N C A R D ] s 16. H o w often d id your as thma W A K E Y O U U P D U R I N G T H E N I G H T dur ing the past w e e k ? [ G R E E N C A R D ] E 17. H o w often did you fee l U N C O M F O R T A B L E b e c a u s e of y o u r as thma dur ing the past w e e k ? [ G R E E N C A R D ] s 18. H o w often d id y o u fee l O U T O F B R E A T H dur ing the pas t w e e k ? [ G R E E N C A R D ] A 19 . H o w often d id you fee l Y O U C O U L D I * " J f E E P U P W I T H O T H E R S b e c a u s e of your as thma dur ing the pas t w e e k ? [ G R E E N O A . 0 - , How often did you have trouble SLEEPING AT NIGHT, because of your asthma, during the past week? [GREEN CARD] How often did you feel FRIGHTENED BY AN ASTHMA ATTACK during the past week? [GREEN CARD] Think about all the activities that you did in the past week. How much were you bothered by your asthma doing these activities? [BLUE CARD] How often did you have difficulty taking a DEEP BREATH in the past week? [GREEN CARD] 221 RESPONSE SHEET NAME: DATES OF COMPLETION (D/M/Y) 1st / / 3rd: / / ITEM 1. Activity 1 2. Activity 2 3. Activity 3 4. Cough 5. Frustrated 6. Tired 7. Worried/Concemed/Troubled 8. Asthma attacks 9. Angry 10. Wheezing 11. Irritable 12. Tightness in chest 13. Feeling different or left out 14. Shortness of breath NUMBER: 2nd: / / 4th: / / RESPONSES 1st 2nd 3rd 4th 6 ITEM 15. Frustrated can't keep up with others 16. Wake up during the night 17. Uncomfortable 18. Out of breath 19. Can't keep up with others 20. Trouble sleeping at night 21. Frightened by asthma attack 22. Bothered in activities overall 23. Deep breath RESPONSES 1st 2nd 3rd 4th 223 7 1. Ball Hockey 2. Baseball 3. Basketball 4. Dancing (ballet/jazz) 5. Football 6. Playing at Recess 7. Playing with Pets 8. Playing with Friends 9. Riding a Bicycle 10. Running 11. Skipping Rope 12. Shopping 13. Sleeping 14. Soccer 15. Swimming 16. Volleyball 17. Walking ACTIVITY SHEET 18. Walking Uphill 19. Walking Upstairs 20. Laughing 21. Studying 22. Doing Household Chores 23. Singing 24. Doing Crafts or Hobbies 25. Shouting 26. Gymnastics 27. Rollerblading/Rollerskating 28. Skateboarding 29. Track and Field 30. Tobogganing 31. Skiing 32. Ice Skating 33. Climbing 34. Getting up in the Morning 35. Talking ACTIVITIES IDENTIFIED BY SUBJECT 5). 2)_ 6)_ 3)_ 7). 4). A p p e n d i x 5 Q O L i F P a t i e n t S p e c i f i c Q u a l i t y o f L i f e Q u e s t i o n n a i r e QOLif Evaluation Form For Parent/Guardian P A R E N T / G U A R D I A N N A M E O F C H I L D D A T E ( M / D / Y ) V I S I T 1 2 © 1996 P O R P O I S E 231 i. For each physical activity listed below, how much has your child been bothered by his or her asthma during the past week? © © © © ® ® ® Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © ( g ) © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © © © Not •bothered Hardly 1 Bothered 1 Somewhat 1 Quite 1 Very j Extremely bothered | a bit | bothered ] Bothered | bothered ] bothered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite 1 Very I Extremely Bothered | bothered | bothered © © © © © to o \ Not bothered Hardly bothered Bothered • bit Somewhat bothered Qui* Bothered Very bomered Extremely 1 bomered © © © © © © © Not bothered Hardly bothered Bothered 1 Somewhat 1 Quile 1 Very I Extremely • bit j bathered | Bothered | bothered | bothered © © © © © © Nat bomered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered 1 Extremely 1 bothered 232 ******* © © © © © (X) © 1 Not bothered | Hardly 1 bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © © © Not bothered Hardly bothered Bothered a hit Somewhat bothered Quite Bothered Very I Extremely bothered 1 bomered © . © © © © © © ~" 1 Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © Very 1 Extremely bothered 1 bothered Not bothered Hardly bothered Bothered a bit Somewhat | Quite bothered | Bothered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered ' Extveuicdy © © © © © © © rta bothered Hardly bothered Bothered • bit Somewhat bothered Quite Bothered Very | Eafcandy © © © © © © © Not bomered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very Eifcuutiy • -* • vovxreo. © © © © © © © Not bothered Hardly bomered Bothered • bit Somewhat bothered Quite 1 Very 1 Exfconery Bomered | bothered 1 bcAered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite I Very 1 Eskaady Bomered | bothered | bomered 233 © ® © © © ® ® N o t bothered Hard!) ' bothered Bothered a bit Somewhat bothered Q u i t e Bothered V e r y bothered Extremely « -• • ® ® ® ® ® ® ® N o t bothered H i r d l y bothered Bothered a bit S o m e w h a t bothered Q u i t e Bothered V e r y bo thered ExCroaicry bomeaod (g) (g) © © O (g) © N o t bothered H a r d l y bothered B o t h e r e d a b i t S o m e w h a t bothered Q u i t e Bothered V e r y b o t h e r e d © © © © © © © N o t bothered H a r d l y bothered B o t h e r e d • bit S o m e w h a t bothered Q u i t e I V e r y 1 Extrcaaery Bothered | b o t h e r e d | b o t h e t o i © © © © © © © N o t bothered H a r d l y bothered B o t h e r e d • b i t S o m e w h a t bothered Q u i t e B o t h e r e d V e r y bo thered bothered © © © © © © © N o t bo thered H a r d l y bothered B o t h e r e d • b i t S o m e w h a t • .1 • u u u i c r c Q Q u i t e ' B o m e r e d V e r y b o t h e r e d © © © © © © © N o t bo thered H a r d l y bothered B o t h e r e d a b i t S o m e w h a t bothered Q u i t e B o t h e r e d V e r y b o t h e r e d Si? © © © © © © © N o t bothered H a r d l y bothered B o t h e r e d a b i t S o m e w h a t bo thered Q u i t e 1 V e r y 1 Tttmrnttf B o t h e r e d | b o t h e r e d | l i i i m r a a i © © © © © © © N o t bo thered H a r d l y bothered B o t h e r e d • b i t S o m e w h a t bo thered Quote B o t h e r e d V c t y | r i f c i n t / b o t h e r e d | b o & e w d 234 2. For each role listed below, how much has asthma bothered your child in each role during the past week? © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered vcr>- Extremely bothered bothenxi @ © © © © ( X ) ( g ) Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very I Extremely bothered I bothered © © © © @ © ) ( g ) Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very I Extremely bothered |. bothered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © © © Not bothered Hardly bothered Bothered • bit Somewhat bothered Quite Bothered Very 1 Extremely bothered 1 buduacd © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely homered © © © © © © © hJot bothered 1 Hardly 1 bothered Bothered a bit Somewhat bothered Quite 1 Very 1 Extremely Bothered 1 bothered 1 bothered © © © © © © © rJr* bothered 1 Hardly 1 bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely homered 235 3. For each social function listed below, how much has your child been bothered by his or her asthma during the past week? © © © © © © © 1 Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely © © © © © © © Not bothered 1 Htrdly 1 bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bomered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bothered © © © © © © ® Not bothered Hardly bothered Bothered • bit Somewhat bothered Quite I Very 1 Extremely Bothered 1 bothered 1 bothered © © © © © © © Not bothered I Hardly 1 bothered Bothered • bit Somewhat bothered Quite Bothered Very j Extremely bothered 1 bomered © © © © © © © Not bothered Hardly bothered Bothered a bit Somewhat bothered Quite Bothered Very bothered Extremely bud wired 236 Patient Specific Quality of Life Questionnaire QOLif Preference Assessment (Physical, Role Function, Social Function) Instructions to Parents/Guardians CHILD ID PARENT DATE (M/D/Y) VISIT 1 2 © 1996 P O R P O I S E 237 1 a. Mark an "X" in each box next to each physical activity that your child likes to do: Physical Activities Arts And Crafts Sports Bake Paint Aerobics Skate Cook Pottery Ball Hockey Skipping Rope Color Sew Basketball Soccer Draw Write Bowling Softball Knit Canoeing Snooker 'Model Building Cycling Stepmaster™ Fish Skiing Football Skip Gymnastics Swim Hike Tennis Hockey Tobogganing Lift Weights Volleyball Run Music And Performance Play And Leisure Clarinet Piano Computers Sleep Dance Saxaphone Drive Smoke Drums Sing Internet Talk Guitar Violin Play with Pets Television Karaoke Play at Recess Toys Read Video Games Shopping Walking b. List any additional activities that your child likes to do: 2. From the physical activities in question 1, which are your child's 3 favourite activities? 238 3. From the physical activities in question 1, which are your child's 3 least favourite activities? 4a. Mark an "X" in each box next to each role that your child does. Roles Babysit School Chores Study Church Take care of pet Dishes Work Religion Vacuum b. List any additional roles that your child does: 5a. Mark an "X" in each box next to each social function that your child is in: Social Functions Camping Friends Circus Movies Clubs Parties Dances Travel Dinner Visit Relatives b. List any additional social functions that your child is in: 239 A p p e n d i x 6 Consent F o r m 240 S T U D Y P R O C E D U R E S This study will consist of questionnaires and interviews. The questionnaires and interviews will occur once during your child's stay in the hospital and again approximately one month after hospital discharge. You and your child may be asked questions about previous medication, about your child's health, and about bis or her health related quality, of life status. Additional information may be obtained from your child's health and/or medication record. Moreover, your child may perform a simple breathing test called Peak Expiratory Flow Rate Monitoring, a routine procedure performed in asthmatic patients that requires less than two minutes to complete. The amount of time to complete both interviews and questionnaires will be approximately forty minutes for the first session and 20 minutes for the second. S I D E E F F E C T S A N D D I S A D V A N T A G E S Your child's participation in this study will not increase his or her risk of known side effects or cause your child to be in any disadvantage compared to other asthmatic children in the hospital. B E N E F I T S However, while your child is participating in this study, study investigators and a committee of health professionals will examine your child's health record for any problems related to the medication that he or she may have taken in the past, while prescribed in the hospital, or will be taking home. This will help ensure that your child is treated with the best medication for his condition. Also, the study assessment tests will be provided free of charge while your child is actively participating in the study. Finally, your child's participation may be help future patients by providing vital information about potentially preventable medication related problems that cause asthma attacks and provide data to help measure the health related quality of life status of asthmatic children. Page 2 of4 242 You are making a decision whether or not to allow your child to participate. Your signature indicates that you have read the information provided above and have decided to allow your child to participate. You will be provided with a copy of this form. SIGNATURE OF PATIENT D A T E PRINT N A M E OF PATIENT SIGNATURE OF PARENT/GUARDIAN D A T E PRINT N A M E OF PARENT/GUARDIAN RELATIONSHIP T O PATIENT SIGNATURE OF WITNESS D A T E PRINT N A M E OF WITNESS SIGNATURE OF INVESTIGATOR D A T E PRINT N A M E O F INVESTIGATOR Page 4 of 4 244 A p p e n d i x 7 Data Co l l ec t ion F o r m 245 DRUG RELATED HOSPITAL ADMISSIONS Patient ID: Medication History Medication/Physician SIG Actual SIG Start | Stop In Community Frequency of Ventolin Use In Hospital Discharge ' . 1 , ' : HOSPITAL ADMISSIONS/DOCTORS VISITS Transfer From: Ward Admission Date: / 19 Discharge Date: / 19 Doctor's Visits Checkups To GP/Year: Urgent Visits (6 Months): Annual Visits Specialist: Urgent Visits (6 Months): Admitted To: Hospital: Diagnosis: Diagnosis: Previous Hospitalizations No. Previous Hospitalizations: No. of Admissions (Last 6 months): Days Hospitalized (Last 6 months): No. of ER Visits In Last 6 Months: Comments: • Where was the child transferred from? • Which hospital ward has the child been admitted to? • Which hospital is the present admission? • When was the patient admitted to the ward? • What was the admission diagnosis? • When was the patient discharged? • What is the discharge diagnosis? • How many times per year does your child see the family doctor for regular checkups for his/her asthma? • How many times per year in the last 6 months have you had to take your child to the child's doctor's office for urgent treatment of asthma or breaming problems? By urgent, I mean mat you had to see the doctor within the next 24 hours. • How many times per year do you take your child to see your specialist for regular check-ups of asthma? • How many times in the last 6 months has your child had to go to the specialist for urgent treatment of asthma or breathing problems? ' • How many times has your child been admitted to hospital for asthma? • How many times in the last 6 months has your child been admitted for asthma? • How many days in total has your child been hospitalized for asthma in the last 6 months? How many times in the last 6 months has your child had to visit a hospital emergency room for urgent treatment of asthma or breathing problems? 247 H I S T O R Y O F A S T H M A Age Breathing Problems First Developed: Other Medical Conditions: History of Present Illness: Mechanical Ventilation: | | Y j jN Premature: Q Y Q N Months Breastfed: Family Hx of Asthma/Allergy/Atopy: Evidence of Infection: 1 . Has your child developed a cold/flu/infection in die last 2 weeks? 2 . Have you noticed any unusual symptoms in the last 2 weeks? 3. Has your child had a runny nose, sore throat, fever, pain? 248 Symptoms Time Of Day Symptoms Occur: •Morning •Afternoon •Evening rjNight rjNo Pattern Pattern O f Symptoms: nDaily •Occasionally Season Symptoms Are Worse: •Summer • F a l l •Winter •Spring QNo Pattern Over the last 4 weeks, how often has he/she experienced the following symptoms: Over the Last 4 Weeks: 2Xor more/day Every Day 3-6X1 week <2XJ week Only at episodes Not at all Chest Tightness Coughing Coughing Up Phlegm Diarrhea/vomiting Fast Heart Beat Headache/migraines Heartburn Itchy skin/rash/watery eyes Night time awakenings Night time mouth breathing Shaky hands/tremor Shortness of breath Stuffy/runny nose Wheezing 249 Triggers Allergies Skin >* > Known Triggers Smokers Mother Father Patient Y/N • • • In the House • • • PPD Smoking: Total No. Smokers: Yes No Cat • • Dog • • What do you think has triggered your child's asthma recently? Does your child have any allergies to any medication? Does your child have any food allergies? Does your child suffer from any eczema, rashes, etc? Are you aware of any triggers in the home or outside that can set off your child's asthma? Does the mother smoke? Does the father smoke? Does the patient smoke? Does anyone smoke in the house? How many packs per day does each one smoke? How many people in the family smoke? Where do they smoke? Has there been an increase, decrease, or no change in the amount of smoking that the family members do? Asthma Management Plan 250 Asthma Effect On QOL Days of School Missed In the Last Year: Role (School) Physical Functioning Sleep Child's Mood Social Functioning • How many days of school has your child missed in the last year? • Is your child worried about his asthma? Does he have some friends? • Would any of these physical activities make your child's asthma worse? Vigorous activities (such as running) Moderate activities (cycling or jumping) Climbing several flights of stairs Walking Temper tantrums T anghmg/crying hard • How would you describe the quality of your child's sleep in the last 4 weeks? • How would you describe your child's mood in the last 4 weeks? 251 Compliance Does your child ever forget to take YES Q NO | | prescription medication? Is your child able to take medication YES Q NO Q at the same time each day? When your child feels better, does YES • NO • your child stop taking any medication? If your child feels worse while taking YES | | NO | | medication, does your child sometimes stop taking it? PARENTS' OCCUPATIONS PEFR ON ADMISSION PEFR IN COMMUNITY 252 Appendix 8 Chronic Symptoms of Asthma Before Hospital Admission (n=54) The following table shows whether each patient had a previous diagnosis of asthma or not, and whether or not each patient had chronic symptoms of asthma before hospital admission. For each case where chronic symptoms of asthma was present, the details of the chronic symptoms are described in the last column. The chronic symptoms have been transcribed from the physicians' notes of each patient's hospital health record and from responses of parents of children during the interviews. Patient Chronic Symptoms Before This Episode Previous Diagnosis of Asthma School Days Missed in the Previous 12 Months Details of Chronic Symptoms 1 Y Y 37 Asthma acts up about every three months. 3 Y Y He has frequent episodes of shortness of breath and coughing associated with colds during the cold weather and exercise. He often has difficulty breathing, in response to cold drinks, exercise, playing a lot, cold weather. He also coughs a lot in such 4 Y Y N A However, before this, "had not had any symptoms." Patient admits he wakes up during the night because of asthma some of the time during the last week. He experiences asthma symptoms after exercising. 5 Y Y N A Longstanding history of poorly controlled asthma 6 Y Y N A Patient feels asthma is not under control 7 Y Y N A N A 8 Y Y 1 No symptoms prior to this episode. 10 Y Y Every time she does any type of exercise she would wheeze and cough. This occurred quite frequently, too frequently to count. Every time she got a cold, her asthma would also become worse. So she takes the influenza vaccination every year. 253 Appendix 8 (cont...) Chronic Symptoms of Asthma Before Hospital Admission (n=54) Patient Chronic Symptoms Before This Episode Previous Diagnosis of Asthma School Days Missed in the Previous 12 Months Details of Chronic Symptoms 11' Y ' Y 1 Patient's asthma attacks seem to come on very quickly without much warning at all. Once attack comes it is hard to thwart it. 12 Y Y .. N A Unwell, distressed, speaks in short sentences, very fidgety. 13 Y Y N A Kunny nose and cough for the past two weeks 15 Y Y 2 Chest tightness, coughing, diarrhea, night-time awakenings, mouth breathing, and shortness of breath only at episodes. 16 Y Y 8 Has been well until 24hours ago, but requires salbutamol 15-17X per week, shortness of breath and stuffy/runny nose only at episodes. 17 Y Y N A Symptoms come and go. Last few years appears that condition is getting better since attacks less frequent. 18 Y Y N A Questionable history of asthma. Patient has used inhalers in the past. 19 Y Y 10 From time of last admission in March patient has been stable until five days ago when sore throat began, together with shortness of breath/cough which began two days ago. He denies chronic cough 254 Appendix 8 (cont...) Chronic Symptoms of Asthma Before Hospital Admission (n=54) Patient s Chronic Symptoms Before This Episode Previous Diagnosis of Asthma School Days Missed in the Previous 12 Months Details of Chronic Symptoms 21 Y Y N A Previously healthy boy until two days ago, when cough with yellow/green sputum jegan 22 Y Y 15 Chest tightness, coughing, diarrhea, vomiting, shaky hands, shortness of breath occur only at episodes, which occur about ten times ear year. 23 Y Y N A Normally does not have any symptoms at all. 24 Y Y N A Wheezes early in the A M every day. Wheezes if she goes jogging and during heavy exercise. 25 Y Y N A Long history of nocturnal cough and wheezing with URTTs but never received any medication for this. 26 Y Y 0 Has has not recently had symptoms in the last couple of months. Previous episodes of colds/flu were no problem. 27 Y Y N A She usually does not have any symptoms. 28 Y Y N A N A 29 Y Y N A N A 30 Y Y N A For 2 years, he has had no symptoms. Completely asymptomatic until 2 days ago when he discovered he had a runny nose and all of a sudden started to cough and wheeze. 255 Appendix 8 (cont...) Chronic Symptoms of Asthma Before Hospital Admission (n=54) Patient Chronic Previous School Details of Chronic Symptoms Symptoms Before This Diagnosis of Asthma Days Missed Episode in the Previous 12 Months 31' Y Y N A She gets A's and B's except for PE, which she gets a C because of her asthma. 32 Y Y 20 Severely asthmatic since age 1. Child reports chest tightness every day. shortness of breath 1-2 X / week. Parents report child usually has no symptoms. 33 Y Y N A Before this cold (URTI) she did not have any symptoms. Did not wake up at night at all. Did not wheeze during sports. Gets a cold about three times per year. 34 Y Y N A For at least two years, she has not had any asthma symptoms. 35 Y Y N A Usually three episodes/year which get treated with bronchodilators and antibiotics. No symptoms between flare-ups. Patient developed a cough and runny nose 2 days before admission. 36 Y Y 20 N A 37 Y Y N A When she has a flare up she begins to get a runny nose, cough which worsens at night, fatigue 38 Y Y 12 Was doing well until yesterday when he started to cough and wheeze overnight; couldn't sleep so mother gave 20 mg prednisone, salbutamol nebules q4h. The attacks are twice weekly requiring salbutamol nebulizer. Child wakes up at night 3-6X/week because of asthma. 256 Appendix 8 (cont...) Chronic Symptoms of Asthma Before Hospital Admission (n=54) Patient Chronic Symptoms Before This Episode Previous Diagnosis of Asthma School Days Missed in the Previous 12 Months Details of Chronic Symptoms «C 39 Y Y N A Lungs get wheezy on humid days. Patient experiences symptoms on and off. Patient well until night prior to admission. 40 Y • Y 20 Coughing at night and during physical activity gets shortness of bream. Normally coughs two times per day, shortness of breath, stuffy nose, and wheezing more than twice daily. 41 Y Y 14 Experiences symptoms mainly from winter to spring during which time he usually has four to six attacks. 42 Y Y N A Known mild asthmatic. 43 Y Y N A Long history of cough and respiratory distress with URTI's-approx. 10-12/ year 44 Y Y N A Diagnosed just 10 months ago 45 Y Y N A Ongoing cough-since he was a baby 46 Y Y N A Symptoms are usually worse in winter. Gets a cold about once every three weeks. Always gives salbutamol when child gets a cold. Symptoms only appear if child gets a cold. Otherwise no symptoms. 47 Y Y N A Has not had any symptoms in the last year. 48 Y Y 1 Two months after discharge, he is still not able to do all the activities that he would like. For example, his mother does not let him do the church activities because she is afraid that he would catch a cold which would trigger his asthma. 50 N N N A First episode of asthma. 51 N N N A First episode of asthma. 52 N N N A First episode of asthma. 257 Appendix 8 (cont...) Chronic Symptoms of Asthma Before Hospital Admission (n=54) Patient Chronic Symptoms Before This Episode Previous Diagnosis of Asthma School Days Missed in the Previous 12 Months Details of Chronic Symptoms 53 < N '• N N A First episode of shortness of breath and cough ever. 54 N N N A First episode of asthma. 55 N N N A Previously healthy boy. Lately, has coughing about once every two to three days. 56 Y Y N A N A 57 N A N A N A N A 60 Y N N A Previously well. He has had the occasional past wheezing and cough for the last year and one half, ever since he started smoking. He has also had some exercise induced cough and wheezing. However, otherwise he has not had any real suggestion of asthma. He has had on and off mild wheezing with upper respiratory tract infections, about two attacks in the last 18-24 months. Nothing was sufficient enough to cause him to come to the hospital, otherwise the remainder of his medical history was negative. 61 Y Y N A N A 258 Appendix 9 Demographic Data of the Study Population (n=54) Each patient's age, gender, ethnic origin, and municipality or city of residence is shown in each row. Patient Age (Years) Gender Ethnicity Residence 1 10.1 Male Caucasian Vancouver 3 5.8 Male Chinese Vancouver 4 , 8.9 Male Chinese Vancouver 5 12.9 Male Chinese Burnaby 6 12.7 Male Caucasian Vancouver 7 5.6 Male Chinese Vancouver 8 12.9 Male Vietnamese Vancouver 10 12.6 Female East Indian Burnaby 11 6.1 Male Filipino Vancouver 12 9.2 Male African Burnaby 13 6.7 Female Japanese Vancouver 15 6.5 Male Caucasian Vancouver 16 10.8 Male Chinese Vancouver 17 8.3 Female Chinese Vancouver 18 9.0 Male Filipino Vancouver 19 16.6 Male Chinese Vancouver 21 5.7 Male Chinese Vancouver 22 5.3 Female Caucasian Vancouver 23 5.1 Male Caucasian Brackendale 24 16.9 Female Vietnamese Vancouver 25 9.5 Female Chinese Vancouver 26 7.3 Female Caucasian Vancouver 27 8.0 Male Caucasian Calgary 28 6.8 Male Caucasian Vancouver 29 7.6 Female Vietnamese Vancouver 259 Appendix 9 (cont...) Demographic Data of the Study Population (n=54) Patient Age (Years) Gender Ethnicity Residence 30 10.8 Male East Indian Vancouver 31 11.4 Female Chinese Vancouver 32 10.7 Male Caucasian Coquitlam 33 9.6 Female Caucasian South Delta 34 11.6 Female First Nation Vancouver 35 5.9 Male Chinese Vancouver 36 ' 9.0 Female First Nation Vancouver 37 5.0 Female Cambodian Vancouver 38 5.6 Male Cambodian Vancouver 39 6.2 Male Chinese Vancouver 40 7.0 Female Chinese Vancouver 41 14.6 Male Chinese Vancouver 42 5.6 Male Caucasian Richmond 43 6.4 Male Caucasian Delta 44 6.8 Female East Indian Vancouver 45 9.4 Male East Indian Surrey 46 5.1 Female Philipino Richmond 47 9.4 Male Chinese Burnaby 48 5.5 Male Caucasian Richmond 50 4.8 Male Philipino Vancouver 51 6.0 Male Chinese Vancouver 52 6.3 Female Sri Lankan Vancouver 53 5.0 Male Caucasian Vancouver 54 6.1 Male Philipino Vancouver 55 11.7 Male Vietnamese Vancouver 56 6.4 Female Caucasian Vancouver 57 8.6 Male Caucasian Surrey 60 15.6 Male Chinese Vancouver 61 10.8 Male Kenyan Vancouver 260 Appendix 10 Physical Characteristics of Patients (N=54) Each Patient's height (cm), height (percentile), weight (kg) and weight (percentile) is shown in each row. Patient Height Height Weight Weight (cm) - (Percentile) (kg) (Percentile) 1 97 93 41.0 85 3 , 111 25 18.0 25 4 126 50 25.0 75 5 163 N A 58.6 N A 6 139 5 32.8 10 7 109 50 16.1 10 8 147 10 34.7 5 10 N A N A 62.2 N A 11 117.5 50 22.4 75 12 135 75 78.8 95 13 116 25 18.4 25 15 N A 25 21.3 25 16 147 75 35.9 50 17 104 50 19.0 10 18 136 75 39.4 95 19 170 N A 52.5 N A 21 115 75 18.3 25 22 112 N A 20.0 60 23 N A N A N A N A 24 N A N A N A N A 25 127 25 22.5 5 26 130 N A 27.5 N A 27 N A N A 23.3 N A 28 N A 25 28.3 90 29 N A N A N A N A 261 Appendix 10 (cont...) Physical Characteristics of Patients (N=54) Patient Height Height Weight Weight (cm) (Percentile) (kg) (Percentile) 30 149 N A 31.0 N A 31 N A N A 36.2 37 32 125 N A 29.3 N A 33 N A , 80 33.9 75 34 150 N A 39.0 N A 35 , 116 98 24.9 75 36 130 23 27.4 45 37 103 25 17.3 25 38 107 25 17.7 25 39 111 25 20.0 10 40 50.5 50 24.9 79 41 163 30 58.3 60 42 115.7 N A 22.0 N A 43 122 90 20.5 40 44 123 50 28.2 95 45 146 95 42.2 95 46 103 10 13.3 5 47 N A N A 25.5 N A 48 103 3 13.2 3 50 112.5 50 25.2 95 51 112 N A 17.9 N A 52 120 75 22.6 60 53 117 95 25.8 50 54 115 35 19.4 25 55 137 5 31.9 10 56 N A N A N A N A 57 N A N A N A N A 60 173 N A 77.3 N A 61 146 90 51.9 105 262 Appendix 11 Clinical Respiratory System Data at Time of Hospital Admission and Changes in Peak Expiratory Flow Rate of Patients Each patient's respiratory rate (breaths per second) and heart rate (beats per minute) is shown in each row. In all cases where data were available, the PEFR improved on discharge. Patient >-HR (beats /min) RR (breaths per minute) Oxygen Saturation Room Air (%) PEFR (mL/min) PEFR (percent predicted) PEFR (mL/min) PEFR (percent predicted) On Admission . On Discharge 1 116 28 94 N A N A 260 95 2 70 24 98 N A N A 300 100 3 150 36 94 N A N A N A N A 4 128 28 96 120 50 210 95 5 138 18 90 220 70 350 100 6 90 20 93 140 50 220 90 7 120 32 92 N A N A N A N A 8 112 26 93 250 74 300 88 9 130 32 90 N A N A N A N A 10 120 24 98 160 50 300 N A 11 160 40 92 100 50 150 75 12 124 28 92 N A N A N A N A 13 140 36 93 100 N A 160 N A 14 130 24 90 110 N A N A N A 15 106 32 86 N A N A N A N A 16 138 36 86 260 79 340 100 17 135 28 97 180 N A N A N A 18 130 25 97 200 73 N A N A 19 110 27 94 400 90 450 100 20 136 24 95 N A N A N A N A 21 130 40 94 N A N A N A N A 22 166 42 88 N A N A N A N A 23 N A N A N A N A N A N A N A 24 N A N A N A N A N A N A N A 25 136 40 96 150 N A 220 N A 26 153 28 89 200 N A 250 N A 27 130 22 94 N A N A N A N A 28 120 28 95 N A N A N A N A 29 N A N A N A 140 N A 200 90 263 Appendix 11 (cont...) Clinical Respiratory System Data at Time of Hospital Admission and Changes in Peak Expiratory Flow Rate of Patients Patient HR RR Oxygen PEFR PEFR PEFR PEFR (beats (breaths Saturation (mL/min) (percent (mL/min) (percent /min) per Room Air predicted) predicted) minute) (%) On Admission 1 On Discharge 30' 80 20 97 200 N A 335 N A 31 170 36 94 200 N A N A N A 32 108 28 90 N A N A N A N A 33 132 24 94 N A N A N A N A 34 68 30 95 N A N A 55 N A 35 140 40 96 135 70 N A N A 36 128 36 93 150 75 N A N A 37 166 52 94 N A N A 110 N A 38 140 28 96 N A N A N A N A 39 140 24 96 N A N A N A N A 40 N A 32 96 N A N A 220 100 41 N A 32 93 150 30 390 80 42 166 28 92 N A N A N A N A 43 140 26 95 100 N A 120 N A 44 120 28 96 130 55 160 70 45 151 40 86 120 50 200 65 46 126 36 94 N A N A N A N A 47 180 38 91 100 N A N A N A 48 160 28 95 150 N A N A N A 49 152 40 94 N A N A N A N A 50 130 48 94 N A N A N A N A 51 130 28 98 N A N A N A N A 52 140 30 92 N A N A N A N A 53 145 40 90 N A N A N A N A 54 138 40 87 N A N A N A N A 55 149 24 95 195 75 270 100 56 N A N A N A N A N A N A N A 57 N A N A N A N A N A N A N A 58 140 32 98 N A N A N A N A 60 48 49 49 157 60 168 65 61 131 30 94 33 13.2 91 45 264 Appendix 12 Estimation of Severity of Acute Exacerbations of Asthma in Children 3 2 Sign/Symptom Mild Moderate Severe PEFR 70-90% predicted or personal best 50-70% predicted or personal best <50% predicted or personal best Respiratory rate, resting or sleeping Normal to 30% increase above the mean 30 - 50% increase above the mean Increase over 50% above the mean Alertness Normal Normal May be decreased Dyspnea Absent or mild; speaks in complete sentences Moderate; speaks in phrases or partial sentences; infant's cry softer and shorter, infant has difficulty suckling and feeding Severe; speaks only in single words or short phrases; infant's cry softer and shorter, infant stops suckling and feeding. Pulsus paradoxus < lOmmHg 10-20 mm Hg 20-40 mm Hg Accessory muscle use No intercostal to mild retractions Moderate intercostal retraction with tracheosternal retractions; use of sternocleidomastoid muscles, chest hyperinflation Severe intercostal retractions wit nasal flaring during inspriation; chest hyperinflation Color Good Pale Possibly cyanotic Auscultation End expiratory wheeze only Wheeze during entire expriation and inspiration Breath sounds becoming audible Oxygen saturation >95% 90-95% <90% P C 0 2 <35 <40 >40 265 Appendix 13 Acute Symptoms of Asthma on Hospital Admission of Patients (n=54) The following table shows the number of days each patient experienced the acute symptoms of the asthma exacerbation prior to hospital admission, the acute symptoms on admission, and the number of days each patient was treated in the hospital. The acute symptoms have been transcribed from the "physicians' notes" of each patient's hospital health record. Patient Number of Days Patient was Symptomatic Prior to Hospitalization Acute Symptoms of Asthma On Hospital Admission Length of Hospital Stay (Days) 1 1 Shortness of breath, bilateral wheeze, cough unresponsive to salbutamol in the emergency room. 2 3 2 Shortness of breath, rhinorrhea, congested cough 2 4 2 Worsening dry cough, shortness of breath, fine exp. and inspiratory wheezes N A 5 2 24 hour history of shortness of breath, chest tightness, and right-sided chest pain. 4 6 N A Decreased air entry to both lungs, bilateral wheeze 4 7 2 Increased shortness of breath, cough, wheezing, lethargy, nasal flaring, bilateral breath sounds, intercostal and subcostal indrawing. 2 8 3 Very wheezy, using accessory muscles to breathe, had expiratory wheeze. Increased coughing, gasping for air. 3 9 N A Shortness of breath, scattered wheezes, decreased air entry to the right base. 2 10 N A Increasing chest tightness, shortness of breath,cough. 3 11 N A Respiratory distress (tachypneic and nasal flare), wheeze, crackles 3 12 3 cold dry cough, severe shortness of breath and wheezing. 3 13 14 Poor air entry to bases, crackles throughout and expiratory wheeze 4 14 2 Worsening respiratory distress, wheeze 1 266 Appendix 13 (cont...) Estimation of Severity of Acute Exacerbations of Asthma in Children Patient Number of Days Patient was Symptomatic Prior to Hospitalization Acute Symptoms of Asthma On Hospital Admission Length of Hospital Stay (Days) 15 N A Harsh congested cough. N A 16 s 1 Difficulty breathing, bilateral wheeze. 6 17 1 Episodic wheezes, mild nasal flare, mild tracheal tug, dry cough 3 18 2 Moderate respiratory distress- inspiratory crackles, expiratory wheeze, shallow breaths 1 19 5 Cough, dyspnea and bilateral wheeze, moderate secretions 2 20 7 On examination, subcostal indrawing, mild intercostal indrawing, slightly decreased air entry, crackles in the left lower lobe. 21 2 Moderate respiratory distress with cough and wheeze, intercostal indrawing 2 22 N A Moderate respiratory distress, slight nasal flaring, slight erythematous rash on face, tracheal tug, subcostal/intercostal indrawing, decreased air entry to bases bilaterally; right > left. 1 23 5 Cough, audible wheeze N A 24 2 N A N A 25 1 Moderate respiratory distress:harsh breath sounds, intrecostal indrawing, use of accessory muscles, very tight chest, bilateral Wheezes 3 26 2 Decreased appetite, shortness of breath, dyspnea, vomiting. N A 27 N A Shortness of breath, vomiting, wheezy chest on right side. 2 28 14 N A 2 29 1 Difficulty breathing 3 30 3 Cough, wheeze, moist cough, not productive, 5 267 Appendix 13 (cont...) Estimation of Severity of Acute Exacerbations of Asthma in Children Patient Number of Days Patient was Symptomatic Prior to Hospitalization Acute Symptoms of Asthma On Hospital Admission Length of Hospital Stay (Days) 31 s 1 Tired, accessory muscle use, chest very tight, decreased A E to bases, decreased breath sounds. 4 32 3 Decreased level of consciousness, grey colour to skin, unable to speak. Vomiting, wheezing. 2 33 2 N A 3 34 N A Unable to speak, as "too tight." N A 35 2 Tight indrawing, tracheal tug, using accessory muscles, diffuse wheezing. 2 36 N A Moderate respiratory distress-intercostal and suprasternal indrawing, marked expiratory wheezes 3 37 3 Nasal flaring, suprasternal and subcostal indrawing, bilateral wheeze 4 38 1 Clean air entry bilateral but full of rhonchi and with prolonged expiration. 2 39 N A Wheeze, congested cough, crackles, trachial tug 2 40 3 mild respiratory distress, poor air entry and inspiratory and expiratory wheezes 2 41 4 Decreased air entry to both bases, chest tightness, cough 3 42 N A Sneezing for 24 hours, shortness of breath, dyspnea. 3 43 3 Decreased air entry with bilateral wheeze-moderate respiratory distress 3 44 N A Decreased breath sounds bilateral with expiratory wheeze, minimal tracheal tug 2 45 14 Severe respiratory distress, wheezes to both lungs 6 46 N A Moderate subcostal indrawing, decreased air entry to both bases, coarse crackles and wheezes bilateral 5 268 Appendix 13 (cont...) Estimation of Severity of Acute Exacerbations of Asthma in Children Patient Number of Days Patient was Symptomatic Prior to Hospitalization Acute Symptoms of Asthma On Hospital Admission Length of Hospital Stay (Days) 47 4 Fever, increased respiratory distress and cough. 3 48' 1 worsening cough, wheeze, shortness of breath 4 49 1 bilateral wheeze with prolonged expiratory phase, coarse rhonchi bilateral, air entry decreased to bases 2 50 1 Diffuse wheezing, marked respiratory distress 2 51 1 Shortness of breath, cough to the point patient could not talk. 2 52 N A Wheezing, trachial tug, shortness of breath and noisy breathing since lunch at school with harsh cough. Worse tonight, 2 53 N A Shortness of breath, slight intercostal indrawing and bilateral wheezes 2 54 2 Moderate respiratory distress-coarse cough with tachypnea, wheezing 1 55 N A Dry paroxysmal cough, shortness of breath, mild fever, use of accessory muscles 4 269 Appendix 14 Chronic Medications and Medications For Current Episode of Patients Evaluated For D R H A (N=44) Patient' Chronic Medications Medications For Current Episode 1 Salbutamol Liquid PRN, Pulmicort 1 puff BID Salbutamol, 3 puffs with no improvement, Ibuprofen 3 Alupent, Tussiaminnic Cough Syrup, Puffer Not .Used No Medications Given 4 Bricanyl PRN (Not Used) Bricanyl At Sign of Symptoms 5 s s Salbutamol MDI 2 Puffs TID, Pulmicort 2X/week Salbutamol Q30 min 6 No Medications Used Salbutamol MDI 100 meg PRN, Becloforte 250 meg BID 7 No Medications Used Salbutamol Mask 4 Times 8 No Medications Used Flovent 1 Puff QID, salbutamol inhaler 1 Puff QID 10 Salbutamol PRN, Pulmicort BID Not Used Salbutamol Q1H 11 Alupent PRN Salbutamol PRN, Beclovent PRN 12 Salbutamol Nebule TID- Not Used, Pulmicort TID Salbutamol NEB Increased Use 13 Salbutamol MDI 2 Puffs Q6H PRN Aerochamber, Becloforte MDI 2 Puffs BID Aerochamber, Also has nebulizer, not used. Salbutamol and Becloforte 15 Salbutamol MDI PRN, Beclovent 2 Puffs QID X 10 Days PRN Aerochamber Increased Salbutamol Use, Benylin 2 teaspoonfuls 16 Salbutamol MDI - 1 MDI per month, Pulmicort Tnhaler Usually BID -Rarely Used, Nebulizer - Not Used Benylin, Increased salbutamol Use, Pulmicort 1 puff 17 Salbutamol PRN MDI Salbutamol MDI PRN 18 No Medications Used Dimetapp PO 19 Salbutamol MDI PRN (Used 1-2 times per month) Salbutamol MDI 21 No Medications Used No Medications Used 22 No Medications Used Salbutamol MDI (Used 2 Doses Before Hospital Admission) 270 Appendix 14(cont...) Chronic Medications and Medications For Current Episode of Patients Evaluated For D R H A (N=44) 23 Salbutamol Nebule BID - Actual Use NA, Pulmicort Nebule BID - Actual UseNA Salbutamol Nebule Up to QID, Pulmicort Nebule BID 24 Salbutamol 1 Puff QD A M Salbutamol 1 Puff QD A M 25 No Medications Used No Medications Used 26 No Medications Used No Medications Used 27 No Medications Used No Medications Used 28 No Medications Used Budesonide Nebule TID, Salbutamol MDI PRN Cold, Salbutamol Nebule, Beclomethasone 5 mg BID 29 Alupent, Salbutamol Nebulizer, Pulmicort Nebulizer Alupent, Salbutamol Nebulizer, Pulmicort Nebulizer 30 No Medications Used Amoxil, Salbutamol Neb 1 dose, Salbutamol Inhaler 1 dose 31 No Medications Used Salbutamol MDI 2 puffs 32 5 mg betamethasone alternate days, Salbutamol nebules 2 mg/mL BID, Pulmicort 0.5 mg Nebules not used. Salbutamol MDI (Used 4-5 puffs) 33 No Medications Used Salbutamol MDI (Used 2 Puffs Q3H) 34 No Medications Used Salbutamol MDI 5-7 Puffs, Beclovent MDI 5-7 Puffs, Prednisone 40 mg, (All Medications Were Expired), No Medications Were Used 35 No Medications Used Benylin and Tylenol 36 Intal Sporadically, Salbutamol Sporadically No Medications Used 37 Tylenol PRN No Medications Used 38 Pulmicort BID, Salbutamol PRN 2X/week 20 mg Prednisone, Salbutamol Nebule Q4H Al l Day and Night 39 Salbutamol MDI PRN Pulmicort MDI 2 Puffs BID X 5 days 40 Salbutamol MDI 5/7 QID, Pulmicort 200 meg 2 puffs BID Salbutamol MDI 5/7 QID, Pulmicort 200 meg 2 puffs BID 41 No Medications Used Salbutamol 5X, Alupent 2 mg/mL 42 Beclovent Via Aerochamber Not Used, Salbutamol MDI Via Aerochamber Beclovent Via Aerochamber Not Used, Salbutamol MDI Via Aerochamber Not Used 271 Appendix 14(cont...) Chronic Medications and Medications For Current Episode of Patients Evaluated For DRHA (N=44) 43 N o Medications Used Salbutamol M D I (Used 1 puff TID for 3 days), Beclovent M D I (Used 1 puf fTIDfor3days ) 44 N o Medications Used N o Medications Used 45 Salbutamol 4 X Per Year, Pulmicort Salbutamol nebules Not Used 46' N o Medications Used Salbutamol M D I 4 puffs, Pulmicort M D I 4 Puffs, Ceclor 2 Doses 47 N o Medications Used Beclofort M D I 2 puffs B I D , Salbutamol M D I 2 puffs T ID 48 Salbutamol M D I 1-2 P uffs QID P R N , Beclovent 2 Puffs 2-4 X daily (Not Used) Beclovent 2 puffs B I D for 1 day, then 1 puff daily for 7 days. 272 A p p e n d i x 15 Results of Eva lua t i on of D R H A The results of the expert panel's evaluation of the presence of an adverse drug reaction, presence of therapeutic failure, degree of significance of symptoms to hospital admission, and degree that each admission was avoidable. Patient Presence of ADR Presence of TF Significance of Symptoms to Hospital Admission Avoidable Admission 1 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 3 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 4 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 5 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 6 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 7 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 8 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 10 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 11 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 12 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 13 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 15 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 16 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 17 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 18 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 273 A p p e n d i x 15 (cont. . .) Results of Eva lua t ion of D R H A Patient Presence of ADR Presence of TF Significance of Symptoms to Hospital Admission Avoidable Admission 19 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 21 >--Unlikely/Unevaluable Definite Dominant Definitely Avoidable 22 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 23 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 24 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 25 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 26 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 27 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 28 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 29 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 30 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 31 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 32 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 33 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 34 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 35 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 274 A p p e n d i x 15 (cont.. .) Results of Eva lua t i on of D R H A Patient Presence of ADR Presence of TF Significance of Symptoms to Hospital Admission Avoidable Admission 36 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 37 Unlikely/U nevaluable Definite Dominant Definitely Avoidable 38 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 39 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 40 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 41 Unlikely/Unevaluable Definite Dominant Definitely Avoidable 42 Unlikely/Unevaluable Possible Dominant Not Evaluated 43 Unlikely/Unevaluable Possible Dominant Not Evaluated 44 Unlikely/Unevaluable Possible Partly Contributing Not Evaluated 45 Unlikely/Unevaluable Possible Dominant Not Evaluated 46 Unlikely/Unevaluable Possible Dominant Not Evaluated 47 Unlikely/Unevaluable Possible Dominant Not Evaluated 48 Unlikely/Unevaluable Possible Dominant Not Evaluated 275 Appendix 16 Asthma Management Before Hospital Admission The following table shows the actions taken by parents and/or the child at the first sign of asthma symptoms related to the hospital admission. Patient Actions Taken At First Sign of Asthma Symptoms 1 Mother increased salbutamol, used a humidifier, and limited physical activities of the patient. 2 Required salbutamol every two hours and mother started on oral steroids 3V Orciprenaline sulfate and over-the-counter cough medication. 4 He was doing well when he had a cough and cold symptoms for the previous two days prior to admission. The cough had increased on the day of the hospital admission and the father gave inhaled turbutaline to the child without much improvement. 5 Salbutamol increased to five to six times per day; one puff of budesonide given. 6 N A 7 36 hours before admission, symptoms began. Inhaled salbutamol and inhaled beclomethasone were given. 8 One day before admission, began taking inhaled salbutamol and inhaled beclomethasone four times daily without significant improvement. 9 No appropriate asthma management therapy was initiated. 10 Used salbutamol by metered-dose inhaler every one hour. 11 Used orciprenaline sulfate at home. 12 Increased use of salbutamol. 13 Gave 1 dose of salbutamol after ninedays of "cough" and wheeze symptoms. 14 Did not implement any treatment. 15 Increased frequency of salbutamol dose. Given Benylin cough medication. 16 Lack of an appropriate asthma management plan. 17 No medications were administered at home. 18 Acute asthma symptoms treated with bropheniramine-phenylepherine. 19 Sporadic use of salbutamol. 20 Two puffs of salbutamol and two puffs of budesonide given. 276 Appendix 16 (cont...) Asthma Management Before Hospital Admission Patient Actions Taken At First Sign of Asthma Symptoms 21 Asthma managed at home with bropheniramine—phenylepherine. 22 Salbutamol X3 and budesonide XI via nebuliizer with no improvement. 23 Symptoms of a cold started five days before admission. Was sneezing, had diarrhea, but had no fever, and no vomiting. Two doses of salbutamol were given. One dose at 4 pm and one dose at 10 pm. Cough worsened, and increased in frequency. 24' No asthma management plan was used. 25 Did not treat acute symptoms at home. 26 No treatment was available. 27 No treatment was available. 28 Began salbutamol and budesonide nebules 3X/day about 2 weeks ago after symptoms started. 29 N A 30 Gave salbutamol only once after two days of symptoms. 31 No asthma treatment plan was used. 32 Increased frequency of salbutamol use. 33 N A 34 Three days ago she started getting the symptoms. Parents gave her salbutamol, inhaled beclomethasone inhalers yesterday. Last night she also got oral steroids. They that it was important to give her medication with the wheezing symptoms but think that maybe they react 35 No treatment was started. 36 No treatment was started. 37 No treatments were given. 38 Mother gave 20 mg prednisone PO and salbutamol Q4H all day. 39 Inhaled beclomethasone 2 puffs BID 40 N A 277 Appendix 16 (cont...) Asthma Management Before Hospital Admission Patient Actions Taken A t First Sign of Asthma Symptoms 41 Orciprenaline sulfate 5 X the day before admission. D i d not use his salbutamol inhaler. 42 Was given salbutamol and inhaled beclomethasone. 43 N A 44 N o asthma treatment was started. 45 N o appropriate acute asthma treatment was given. 4 6 ' M o m gives salbutamol TID and pulm TID when she has an U R T I (via neb) 47 Father started patient on inhaled beclomethasone (400 ug BID) and salbutamol T ID when symptoms began to appear about 4 days ago. 48 N A 49 N o previous knowledge about asthma. 50 N A 51 First episode of asthma. 52 N A 53 N A 54 N A 55 N A 278 Appendix 17 Classification of Asthma Severity Patient Chronic Severity 1 M I L D - P E R S I S T E N T 3 M I L D - I N T E R M I T T E N T 4 M I L D - P E R S I S T E N T 5 M O D E R A T E - P E R S I S T E N T 6 M I L D - P E R S I S T E N T 7 M I L D - I N T E R M I T T E N T 8 . M I L D - I N T E R M I T T E N T 10 M O D E R A T E - P E R S I S T E N T 11 M I L D - I N T E R M I T T E N T 12 M I L D - P E R S I S T E N T 13 M I L D - P E R S I S T E N T 15 M I L D - I N T E R M I T T E N T 16 M O D E R A T E - P E R S I S T E N T 17 M I L D - I N T E R M I T T E N T 18 N O N - D E T E R M I N A B L E 19 M I L D - P E R S I S T E N T 21 M I L D - I N T E R M I T T E N T 22 M I L D - P E R S I S T E N T 23 M I L D - P E R S I S T E N T 24 M O D E R A T E - P E R S I S T E N T 25 M I L D - P E R S I S T E N T 279 Appendix 19 (cont...) Classification of Asthma Severity Patient Chronic Severity 26 N O N - D E T E R M I N A B L E 27 M I L D - I N T E R M I T T E N T 28 N O N - D E T E R M I N A B L E 29 M I L D - P E R S I S T E N T 30 M I L D - I N T E R M I T T E N T 31 M I L D - P E R S I S T E N T 32 • M O D E R A T E - P E R S I S T E N T 33 M I L D - I N T E R M I T T E N T 34 M I L D - I N T E R M I T T E N T 35 M I L D - I N T E R M I T T E N T 36 M O D E R A T E - P E R S I S T E N T 37 N O N - D E T E R M I N A B L E 38 M O D E R A T E - P E R S I S T E N T 39 M I L D - I N T E R M I T T E N T 40 M I L D - P E R S I S T E N T 41 M I L D - P E R S I S T E N T 42 M I L D - P E R S I S T E N T 43 N O N - D E T E R M I N A B L E 44 M I L D - I N T E R M I T T E N T 45 M I L D - P E R S I S T E N T 46 M I L D - I N T E R M I T T E N T 47 N O N - D E T E R M I N A B L E 48 M I L D - P E R S I S T E N T 280 Appendix 18 Inhaled Steroids Use and Oral Steroid Use Before Hospital Admission of Patients The presence or absence o f inhaled steroid use and oral steroid use is shown in each row. Patient D i d the patient take any inhaled steroids for the acute exacerbation? D i d the patient take any oral steroids for the acute exacerbation? 1 N O N O 3 N O N O 4 Y E S N O 5 N O N O 6 Y E S N O 7 N O N O 8 Y E S N O 10 N O N O 11 Y E S N O 12 N O N O 13 Y E S N O 15 N O N O 16 Y E S N O 17 N O N O 18 N O N O 19 N O N O 21 N O N O 22 N O N O 23 N O N O 24 N O N O 25 N O N O 26 N O N O 27 N O N O 28 Y E S Y E S 29 Y E S N O 30 N O N O 31 N O N O 32 N O N O 281 Appendix 18 (cont...) Inhaled Steroids Use and Oral Steroid Use Before Hospital Admission of Patients Patient D i d the patient take any inhaled steroids for the acute exacerbation? D i d the patient take any oral steroids for the acute exacerbation? 33 N O N O 34 YES YES (medication expired 2 years ago) 35 N O N O 36 N O N O 37 N O N O 3 8 ' N O YES 39 YES N O 40 YES N O 41 N O N O 42 YES N O 43 YES N O 44 N O N O 45 N O N O 46 YES N O 47 YES N O 48 YES N O 282 Appendix 19 Compliance With Medications Before Hospital Admission Patient Compliance Details of Non-compliance 1 Non-compliant Budesonide started one year ago on twice daily dosing and he misses the occasional dose. Child forgets to take medication sometimes. Does not always take the medication at the same time each day. If he feels better, he would stop taking medication on his own. 3 ' Non-compliant Has had difficulty using the puffer so did not use it at all. 4 Non-compliant Had been prescribed terbutaline sulphate one year ago. This was the only medication he had been prescribed (no other meds). However, previous to this episode, he had not used it. 5 Non-compliant Was on one puff of budesonide twice daily, but he reported taking it about twice weekly even though he requires salbutamol three to four puffs daily. 6 Not enough data Puffer technique was poor. 7 Compliant Not applicable. 8 Non-compliant Dr. had prescribed Flovent 50ug four times daily on a regular basis, but he did not take it regularly. 10 Non-compliant She did not use her budesonide. Mom frustrated with frequency of medication use and seeking a traditional medicine through a "naturalpath." 11 Non-compliant Medication was just given in bursts. Either the medication was running out or he was not given it. 12 Non-compliant Patient was non-compliant. Does not increase dose of budesonide as instructed, only increases dose of salbutamol. 13 Non-compliant Did not administer the preventative medication. 15 Not enough data Not applicable. 16 Non-compliant Salbutamol had been used about 15 to 17 times per week. Rare use of budesonide MDI. 17 Non-compliant No medications were given by parents before going to ER atBCCH. 18 Not enough data Not applicable. 19 Not enough data Not applicable. 283 Appendix 19 (cont...) Compliance With Medications Before Hospital Admission Patient Compliance Details of Non-compliance 21 No previous asthma medications Not applicable. 22 Not enough data Not applicable. 23 Compliant Not applicable. 24 « - — Non-compliant Non-compliant with nedocromil sodium inhaler therapy ever since the patient moved to Vancouver. 25 ' No previous asthma medications Not applicable. 26 No previous asthma medications Not applicable. 27 Not enough data Not applicable. 28 Non-compliant Poor compliance according to family physician. 29 Not enough data Not applicable. 30 Not enough data Not applicable 31 Non-compliant Patient's reported use of medication is not consistent. Parents do not appear to be very involved in her management. They do not come to visit her. 32 Non-compliant Child reports that the parents can't afford the corticosteroid medications. That is why they only have the salbutamol at home. 33 Not enough data. Not applicable. 34 Non-compliant Corticosteroids taken were expired 2 years ago. 35 No previous asthma medications Not applicable. 36 Non-compliant. Did not take inhaled corticosteroids regularly. 37 No previous asthma medications Not applicable. 38 Non-compliant Mother sometimes forgets to give the medication. 39 Compliant Not applicable. 40 Non-compliant Poor technique with budesonide inhaler. 41 Non-compliant Did not use his salbutamol puffer. Inappropriate chronic asthma management. Does not use his spacer. 42 Non-compliant Did not use inhaled corticosteroids as directed. 43 Non-compliant Upon diagnosis two weeks ago, patient was given salbutamol and beclomethasone dipropionate inhalers but only used them on and off. 44 Non-compliant Did not take medications as directed. 284 Appendix 19 (cont...) Compliance With Medications Before Hospital Admission Patient Compliance Details of Non-compliance 45 Non-compliant Salbutamol used four times per year during acute attacks and budesonide is not used. 46 Compliant Not applicable. 47 Non-compliant Previous medications were salbutamol and beclomethasone dipropionate as needed, but had not been taking them since last year. 48 Non-compliant Mother is not compliant with medication because she is afraid o f the side effects. 285 

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