Who Received Oral Or Inhaled Corticosteroids During the Preceding 2 Weeks
KARNATAKA, BANGALORE
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATE & ADDRESS / DR. RAMYA
POSTGRADUATE
DEPARTMENT OF PAEDIATRICS,
KARNATAKA INSTITUTE OF MEDICAL SCIENCES, HUBLI-580022
2. / NAME OF THE INSTITUTION / KARNATAKA INSTITUTE OF MEDICAL SCIENCES, HUBLI-580022
3. / COURSE OF STUDY AND SUBJECT / MD IN PAEDIATRICS
4. / DATE OF ADMISSION TO THE COURSE / 31ST MAY 2012
5. / TITLE OF TOPIC / “COMPARISON OF NEBULISED ADRENALINE,ORAL DEXAMETHASONE, AND NEBULISED ADRENALINE PLUS ORAL DEXAMETHASONE IN THE TREATMENT OF BRONCHIOLITIS”
6. / BRIEF RESUME OF INTENDED WORK:
6.1 NEED FOR STUDY:
Bronchiolitis is the most common lower respiratory tract infection in infancy. It is a clinically diagnosed respiratory condition presenting with breathing difficulty, cough, poor feeding, irritability and, in the very young, apnea. These clinical features, together with wheeze and/or crepitations on auscultation help to make the diagnosis.1 Bronchiolitis most commonly presents in children aged less than 2 years.2 It is most commonly caused by viruses, with the leading cause being respiratory syncitial virus.1
The burden of the disease is significant.Overall it is estimated that 11% to 12% of all infants are affected in the first year of life out of which 3% need hospitalisation1.The rate of admissions to hospital with bronchiolitis has increased over the past 10 years. The reasons for this are not fully understood and are likely to be multifactorial and include improved survival of preterm infants.3
The current treatment of bronchiolitis is controversial.Bronchodilators and corticosteroids arewidely used but not routinely recommended.4A meta-analysis of the treatment effects of nebulisedselective beta-agonists failed to show anyconsistent benefits,5 whereas a meta-analysis of thetreatment effects of nebulised adrenaline suggested a decrease in clinical symptoms as comparedwith either placebo or salbutamol.1 In onesmall, randomized, controlled trial, treatment withdexamethasone led to a 40% relative reduction in admission rates as compared with placebo.6However, a large, recently published study of dexamethasone, failed to show any difference in hospital-admission rates or respiratory clinical scoresas compared with placebo.7
The use of nebulised adrenaline, systemic corticosteroid and both in the treatment of bronchiolitis in infants is still in controversy. Hence the current study is undertaken to compare the efficacy ofnebulised adrenaline alone, ashort course of oral dexamethasone alone and both, in decreasing the respiratory distress and duration of hospital stayamong children with bronchiolitis admitted in KIMS, Hubli.
6.2 REVIEW OF LITERATURE:
1. In a randomized control trial ( RCT) conducted by Kuyucu et al,69 infants aged 2–21 months with bronchiolitis were divided into 4 groups:
1) Intramuscular Dexamethasone +Inhaled Adrenaline
2) Intramuscular Dexamethasone +Inhaled Salbutamol
3) Intramuscular Placebo+Inhaled Adrenaline
4) Intramuscular Placebo+Inhaled Salbutamol
Primary outcomes were assessed in terms of clinical scores (heart rate, respiratory rate, Respiratory Distress Assessment Instrument (RDAI))with no significant differences between the primary outcome variables of the 4groups within the first 2 hrs and at 24 h. Significant differences were noted on the 5th day on RDAI score in all groups, butthe outcome in Group 1was better than that in Group 3 (p=0.02) and Group 4 (p=0.000),the outcome in Group 2 was better than that in Group 4 (p=0.01). Secondary outcomes in terms of respiratory signs and symptoms were assessedand they were lesser in dexamethasone groups(Groups 1 and 2), but this was not statistically significant.
The authors concluded that the combination of intramuscular dexamethasone and inhaled adrenaline was beneficial in reducing duration of symptoms and length of hospitalization.8
2. Bentur et al conducted an RCT on 61 infants aged 3–12 months with bronchiolitis admitted to hospital and divided them into 2 groups:
1)Inhaled Dexamethasone+Inhaled Adrenaline
2)Inhaled Placebo+Inhaled Adrenaline
Primary outcomes were assessed in terms of clinical scores (respiratory rate, wheezing, retraction, general condition, oxygen saturation), duration of supplemental oxygen, duration of intravenous fluidswith no significant differences. Secondary outcomes in terms of discharge rate with the cumulative proportion of, inhospital stay of patients, was lower in the treatment of inhaled dexamethasone+inhaled adrenaline group than in the placebo group, mainly on days 5 (40% vs. 75%) and 6, after hospitalisation (30% vs. 60%) (p<0.038). Length of hospitalisation in premature infants was 2.6 days shorter in the inhaled dexamethasone+inhaled adrenaline group compared to the placebogroup ( 6.5±1.7 vs. 9.1±1.9 days, respectively).
It was concluded that theduration of hospital stay was reduced in inhaled dexamethasone plus inhaled adrenaline group compared with inhaled placebo plus inhaled adrenaline group.9
3. In an RCT conducted by Plint et al, 800 infants aged 6 weeks–12 months with bronchiolitis, were divided into 4 groups:
1) Oral Dexamethasone+Inhaled Adrenaline
2)Oral Placebo+Inhaled Adrenaline
3) Oral Dexamethasone+Inhaled Placebo
4)Oral Placebo+Inhaled Placebo
Primary outcome in terms of hospital admission upto 7 days after enrollment into the study was assessed. There was reduction in hospital admission on 7th day in oral dexamethasone+inhaled adrenaline group. Secondary outcomes in terms of shortening of time to discharge and duration of symptoms (e.g. respiratory rate, heart rate) was assessed, resulting in earlier discharge from medical care in oral dexamethasone+inhaled adrenaline group than in the placebo group (4.6 vs. 5.3 days), and faster resumption of quiet breathing (and normal feeding in the oral dexamethasone+inhaled adrenaline group than in the placebo group) i.e. by 7th day, 34 infants (17.1%) in the inhaled adrenaline+oral dexamethasone group, 47 (23.7%) in the adrenaline group, 51 (25.6%) in the dexamethasone group, and 53 (26.4%) in the placebo group had been admitted to the hospital. Only the infants in the inhaled adrenaline+oral dexamethasone group were significantly less likely than those in the placebo group to be readmitted by day 7 (relative risk, 0.65; 95% confidence interval, P=0.02).
The study concluded that the combination of oral dexamethasone and inhaled adrenaline shortened the duration of symptoms and time of discharge with earlier return to normal activity.10
4. A cost effective analysis conducted by Sumner A, Patel H, Bhatt M et al, found the combination of nebulised adrenaline+oral dexamethasone was both, the most effective and least costly. Average societal costs were $1115 for the combination therapy, $1210 for no active treatment, $1322 for adrenaline alone, $1360 for dexamethasone alone. The average time to the curtailment of all symptoms was 12.1 days for the combination therapy, 12.7 days for no active treatment, 13.0 days for adrenaline alone, 12.6 days for dexamethasone alone.
The study indicated that the combination of nebulized epinephrine plus oral dexamethasone is the most cost-effective treatment option, because it is not only effective in controlling symptoms but also it is associated with the least costs. 11
5.Hartling et al conducted a meta-analysis of 48 trials (4897 patients, 13 comparisons) on bronchiolitis and concluded that adrenaline only group had reduced admission on day 1 by 33% compared to placebo while the combination oforal dexamethasone and inhaled adrenaline had reduced admissions on day 7 by 35% compared to placebo. This showed the effectiveness and superiority of adrenaline for clinical outcomes among outpatients. 12
6. In another systematic review, a Cochrane study, Hartling et alfound 19 studies, involving 2256 children that used adrenaline for the treatment of bronchiolitis in acute care settings. When comparing adrenaline with placebo, no differences were found for length of hospital stay but there was some indication that adrenaline was effective for reducing hospital admissions. One large, high-quality trial suggested that combined treatment with systemic glucocorticoids (dexamethasone) and adrenaline may significantly reduce admissions. Thus the evidence is that adrenaline is more effective than placebo for bronchiolitis in outpatients. Recent research suggests combined epinephrine and steroids may be effective for outpatients.13
7. In a study conducted by Modaressi MR et al, 40 infants aged 1 month to2 yrs with acute bronchiolitis were enrolled into 2 groups :
1) Nebulised Adrenaline
2) Nebulised Salbutamol
Mean hospitalization duration was 3.3±1.1 and 3±0.9 days in the patients receiving salbutamol and adrenaline, respectively (P=0.03). There was a significant difference in assessing RDAI score between thetwo groups (P=0.03). But no differences in SpO2, PR, or RR variables (p<0.05).
The study led to the conclusion thatusing adrenaline instead of salbutamol could be more effective in the management of acute bronchiolitis.14
6.3OBJECTIVES OF STUDY:
To compare the effectiveness ofnebulised adrenaline, oral dexamethasone andcombination of both nebulised adrenaline and oral dexamethasone on bronchiolitis in terms of clinical improvement, decrease in respiratory distress andduration of hospital stay.
7. / MATERIALS AND METHODS:
7.1 Source of data:
Children in the age group of 4 weeks to 2yrs with bronchiolitis admitted into the Pediatrics ward, KIMS, Hubli.
7.2 Type of the study:
Hospital based prospective interventional non blinded randomized trial.
7.3 INCLUSION CRITERIA:
All cases of acute bronchiolitis with a Respiratory Distress Assessment Instrument (RDAI) 15scoreof 4 to 15 [on a scale of 0 (mild) to 17 (severe)].
7.4EXCLUSION CRITERIA:
The following children will be excluded from the study-
- Who received oral or inhaled corticosteroids during the preceding 2 weeks
- Who have had a previous episode of wheezing
- Who have a known chronic cardiopulmonary disease
- Who are immunodeficient
- Who have had exposure to varicella within the preceding 3 weeks
- Who present with severe respiratory distress (pulse > 200/min, respiratory rate > 80.min, or RDAI score above 15) or profound lethargy/ altered sensorium
- Who are preterms with corrected age of less than 4 weeks at presentation
- Whose parents have not given consent
- Methods of collection of data:
7.6 Sample Size:
Since this is a time bound study, during the study period, all children who fulfill the inclusion criteria will be enrolled.
7.7 Diagnosis:
Diagnosis is mainly clinical, based on the presence of, nasal discharge, wheezy cough, fine inspiratory crackles and/or high pitched expiratory wheeze.
7.8 Monitoring:
Monitoring will be done by measuring the oxygen saturation with pulse oximeter and the clinical status including the RDAI score, every 30min for the first 2 hours, every hourly for the next 4 hours and then every 6thhourly during the hospital stay. However, based on the child’s condition the frequency of monitoring will be increased if necessary.
7.9 Investigations:
Chest X-ray and other routine investigations will be done
7.10 Treatment:
Supportive treatment like supplemental oxygen, intravenous fluids and antipyretics will be given to all the children. When indicated antibacterial drugs will be added.
The interventions to be compared will be divided into 3 groups of treatment:
Group 1: Nebulised Adrenaline
Group 2: Oral Dexamethasone
Group 3: Combination of Nebulised Adrenaline and Oral Dexamethasone
7.11 Procedure:
The medication dosages would be:
- Nebulised adrenaline 3ml in 1:1000 solution per treatment every 6thhourly for 6 days or till discharge, whichever is earlier.
- 6 oral doses of Dexamethasone suspension 1mg/kg (max 10 mg) per day on day 1 followed by 0.6mg/kg (max 10 mg) per day for additional 5 days or till discharge, whichever is earlier.
Outcomes will be measured in terms of improvement in oxygen saturation, clinical assessment including RDAI score and the duration of hospital stay.
7.13Criteria for discharge:
- Improvement in RDAI score to <4.
- Absence of other conditions requiring inpatient treatment.
“Yes”
Chest x-ray and routine blood and urine examination will be done in all patients.
7.15 Has the ethical clearance been obtained from ethical committee of your Institution:
“Yes”, ethical clearance has been obtained.
7.16 Statistical Analysis
Appropriate tests like t-test and Chi-square test will be used for analysis of results.
8. / LIST OF REFERENCES:
- Hartling L, Weibe N, Russell K, Patel H, Klassen TP. A meta-analysis of randomized controlled trials evaluating the efficacy of epinephrine for the treatment of acute viral bronchiolitis. Arch Pediatr Adolesc Med. 2003; 157: 957-964.
- Zorc JJ, Hall CB. Bronchiolitis: Recent evidence on diagnosis and management. Paediatrics. 2010; 125: 342-349.
- Scottish Intercollegiate Guidelines Network. Bronchiolitis in children. A national clinical guideline. 2006. SIGN publication, 91, Edinburg (Scotland): Scottish Intercollegiate Guidelines Network.
- American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Pediatrics. 2006; 118: 1774-1793.
- Flores G, Horwitz RI. Efficacy of beta2-agonists in bronchiolitis: a reappraisal and meta- analysis. Pediatrics. 1997; 100: 233-239.
- Schuh S, Coates AL, Binnie R, Allin T, Goia C, Corey M, Dick PT. Efficacy of oral dexamethasone in outpatients with acute bronchiolitis. J Pediatr. 2002; 140: 27-32.
- Corneli HM, Zorc JJ, Mahajan P, Scott D, Kathy N, Malik B et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med. 2007; 357: 331-339.
- Kuyucu S, Unal S, Kuyucu N, Yilqor E. Additive effects of dexamethasone in nebulized salbutamol or L-epinephrine treated infants with acute bronchiolitis. Pediatr Int.2004; 46: 539–544.
- Bentur L, Shoseyov D, Feigenbaum D, Gorichovsky Y, Bibi H. Dexamethasone inhalations in RSV bronchiolitis: a double-blind, placebo-controlled study. Acta Paediatr.2005; 94: 866-871.
- Plint AC, Johnson DW, Joubert G, Black KJ, Turner T, Whitehouse S et al.Epinephrine and dexamethasone in children with bronchiolitis. N Engl J Med. 2009; 360: 2079-2089.
- Sumner A, Coyle D, Mitton C, Jonhson DW, Patel H, Klassen TP et al. Cost-effectiveness of Epinephrine and Dexamethasone in children with bronchiolitis. Pediatrics. 2010; 126: 623-631.
- Hartling L, Fernandes RM, Bial L, Milne A, Johnson D, Plint A et al. Steroids and bronchodilators for acute bronchiolitis in the first two year of life, systematic review and meta-analysis. BMJ. 2011; 342: 1714.
- Hartling L, Bialy LM, Vandermeer B, Tjosvold L, Johnson DW, Plint AC et al. Epinephrine for acute viral bronchiolitis in children less than two years of age. Cochrane Database of Systematic Reviews. 2011.
- Modaressi MR, Asadian A, Faghihinia J, Arashpour M, Mousavinasab F. Comparison of epinephrine to salbutamol in acute bronchiolitis. Iran J Pediatr. 2012; 22: 241-244.
- Lowell DI, Lister G, Von Koss H, McCarthy P. Wheezing in Infants: the response to epinephrine. Pediatrics. 1987; 79: 939-945.
9. / SIGNATURE OF CANDIDATE
10. / REMARKS OF THE GUIDE / RECOMMENDED.
11. / NAME & DESIGNATION
11.1 GUIDE / DR. DEVARAJ V. RAICHUR
PROFESSOR
DEPARTMENT OF PAEDIATRICS
KIMS, HUBLI.
11.2 SIGNATURE
11.3 HEAD OF THE DEPARTMENT / DR. T. A. SHEPUR
PROFESSOR AND HOD
DEPARTMENT OF PAEDIATRICS
KIMS, HUBLI.
11.4 SIGNATURE
12 / 12.1 REMARKS OF CHAIRMAN AND PRINCIPAL
12.2 SIGNATURE