A 3-day course of 1 mg/kg versus 2 mg/kg bodyweight prednisolone for 1- to 5-year-old children with acute moderate exacerbation of asthma: a randomized double-blind noninferiority trial

Abstract

Background

Even though the guidelines on the management of preschool asthma recommend early use of corticosteroids for acute moderate-to-severe exacerbations, considerable variation exists with regard to type and dose of steroids.

Objectives

To compare the clinical outcomes and side effect profile between 1 mg/kg/day and 2 mg/kg/day of oral prednisolone when administered for 3 days in preschool children with acute moderate asthma exacerbations.

Study Design and Setting

Randomized double-blind noninferiority trial was done in the paediatric emergency of a teaching hospital.

Patients, Interventions, and Outcomes

A total of 128 children aged 1 to 5 years who presented to the paediatric emergency with acute moderate exacerbation of asthma were enrolled. They were randomized into two groups. One group received 1 mg/kg/day and the other 2 mg/kg/day of oral prednisolone for 3 days. Severity of asthma exacerbation was measured by Pediatric Respiratory Assessment Measure (PRAM) score. The PRAM scores, wheeze recurrence, and side effect profile were compared and analyzed between the two groups.

Results

The difference in the PRAM scores at 1, 2, 3, and 4 hours after intervention between the two groups was statistically insignificant. Need for escalation of therapy, salbutamol nebulization, time for resolution of symptoms, and recurrence of wheeze were similar between the two groups. Vomiting was significantly less frequent in low-dose group with a relative risk of 0.19 to 0.99 compared to high-dose prednisolone.

Conclusion

Prednisolone at a dose of 1 mg/kg/day was not inferior to 2 mg/kg/day in terms of clinical improvement and recurrence of wheeze within 1 week and has less frequent vomiting compared to higher dose.

Recommendations for the treatment of young children with asthma are weak due to the scarcity of trials in this age group and are largely extrapolated from the data on older children (1). Guidelines on the management of preschool asthma recommend early use of corticosteroid in acute moderate-to-severe exacerbations (2–5). However, the role of steroids, the dose, route of administration, and duration has not been convincingly studied in young children. The Global Initiative for Asthma (GINA) guideline recommends 1 mg/kg/day to 2 mg/kg/day of steroids to be administered for 3 to 5 days (2). The Australian guidelines recommend 1 mg/kg/day of steroids for 5 days (3). British guidelines recommend 20 mg/day of steroids for 3 days in preschool children (4). Indian practice guidelines recommend 1 mg/kg/day to 2 mg/kg/day for 3 to 7 days but they are not specific for 1- to 5-year-old children (5). In a study by Chang et al., the authors concluded that a 5-day course of 1 mg/kg/day of prednisolone is not superior to a 3-day course in nonhospitalized children in terms of symptom-free interval or quality of life (6). Side effects associated with steroid administration include vomiting, abdominal pain, anxiety, aggressive behaviour, and sleep disturbances (7). These side effects were found to be more frequent with the use of a higher dose of prednisolone, 2 mg/kg/day (8). Hence, due consideration must be given while choosing the dose as well as duration of steroids for treatment of exacerbations. There are no previous studies comparing the efficacy and side effects of low-dose and high-dose prednisolone in the 1 to 5 years age group and hence the need for this study.

METHODS

This trial was conducted in the paediatric triage of a teaching hospital over a period of 2 years from July 2016 to July 2018. The aim of this study was to evaluate the difference in the clinical outcome and side effect profile between 1 mg/kg/day and 2 mg/kg/day of oral prednisolone (administered for 3 days) for the treatment of acute moderate exacerbations of asthma in children aged 1 to 5 years. The primary objective of this study was to examine the efficacy of two drug dosage regimens of oral prednisolone in children aged 1 to 5 years with a moderate exacerbation of bronchial asthma, in terms of the reduction of the severity of the asthma exacerbation over time. The secondary objectives were to assess and compare the number of children who required escalation of treatment, had a recurrent attack of asthma within 1 week of index visit, and the side effect profile between the two groups. This study was approved by the Post Graduate Research Monitoring Committee (PGRMC) and Institute Ethics Committee for Human Studies (IEC-HS) of our hospital. This trial was registered in Clinical Trial Registry of India (CTRI) with CTRI/2017/08/009297 as its registration number. Children aged 1 to 5 years who attended paediatric triage with wheeze were considered for enrolment. The diagnosis of asthma was made clinically as per the definition given by the Canadian Thoracic Society (9). Children aged 1 to 5 years who fulfilled the above criteria for the diagnosis of asthma and with moderate exacerbation of asthma (as evidenced by a Pediatric Respiratory Assessment Measure [PRAM] score of 4 to 7) at the time of presentation to triage were included for the study. Children with clinical evidence of other known chronic respiratory conditions such as bronchiectasis, cystic fibrosis, congenital airway anomalies, and recurrent aspiration in the past were excluded. Also those with clinical suspicion of pneumonia, congenital heart disease, failure to thrive, children who were already on prednisolone, Montelukast, or azithromycin therapy, and those with poor oral intake, drowsiness, vomiting, or features of life-threatening asthma were excluded from the study.

Children aged 1 to 5 years presenting to paediatric triage with the complaints of wheeze comprised the sample population. Assuming a minimum expected noninferiority difference in the PRAM score at 4 hours after enrolment between the groups as 0.4 with a standard deviation of 0.8, power of 80%, and alpha error of 5%, the sample size was calculated to be 128, that is 64 in each group. The sample size was calculated using power and sample size calculator software. Sequential sampling technique and computer-generated block randomization were used in this study. This study was conceived as a randomized double-blind parallel group noninferiority trial with an allocation ratio of 1:1. The randomization list was prepared from the website ‘sealedenvelope.com’.

An opaque envelope with an alphanumeric code written on top of it (used by the investigator for identification purposes) was issued to each of the enrolled participants and inside a card was placed which mentioned the dose of prednisolone to be administered (either 1 mg/kg/day or 2 mg/kg/day) as per the randomization list provided by the ‘sealedenvelope.com’ website. The unopened envelope containing the card was handed over to a designated nursing officer who would issue prednisolone tablets as per the dose written on the card. The nursing officer administered the pounded tablets in a powdered form mixed with water and also gave the required quantity of drugs, in small packets to the parent, to be powdered and administered with water on days 2 and 3.

Children who met the inclusion criteria (PRAM score 4 to 7) were enrolled into the study after obtaining informed consent from parents. Thereafter, the children were randomly assigned to either 1 mg/kg/day group or 2 mg/kg/day group as per the computer-generated block randomization list. Both groups received three doses of salbutamol nebulization (2.5 mg for <20 kg; 5 mg for more than 20 kg) along with ipratropium nebulization (500 mcg) at every 20-minute interval in the first hour. Sixty-four children of group A had received 1 mg/kg/day of prednisolone as single oral dose within 1 hour of initial nebulization and were advised to continue the same for a total of 3 days. Likewise, the other group of 64 children who belonged to group B received 2 mg/kg/day of prednisolone as a single oral dose within 1 hour of initial nebulization and were advised to continue the same for a total duration of 3 days. The subsequent need for nebulization was decided on an individual case by case basis by the treating physician. Primary assessment was done which included PRAM scores and was analyzed at hourly intervals during the initial 4 hours for all the children. After completion of 4-hour duration, if the PRAM score is <4, the child was discharged from triage with advice to complete the rest of the prednisolone doses along with oral salbutamol (0.15 mg/kg/dose TDS for 3 days). No further assessment of PRAM score was performed for these children. For the children who continued to have a PRAM score of ≥4 after 4 hours of intervention, PRAM score was assessed at 8, 24, 48, and 72 hours or until they were discharged, whichever was earlier. These children were discharged once their PRAM score was <4 and no further PRAM score was assessed after discharge for these children. The PRAM score was calculated by the primary investigator alone to avoid interobserver variability. For children who did not improve on this therapy, intravenous magnesium sulphate and Terbutaline injection were administered on a case-to-case basis as decided by the treating physician. Discharged children were reviewed after 1 week in the asthma follow-up clinic to enquire about the time for symptom resolution, recurrence of wheeze, compliance to drugs, and side effects. Statistical analysis was carried out using IBM SPSS software version 19.

RESULTS

A total of 172 children of preschool age group were considered for enrolment in the study. Of this group, 38 candidates were excluded as they met at least one of the exclusion criteria. An additional six children were excluded as their parents refused consent to participate. Hence, a total of 128 children were enrolled and subjected to randomization. Primary assessment was done for all 128 children. Since a few children were lost to follow-up and a few children had not completed the entire prednisolone course, the analysis of side effect profile was limited to 103 participants alone (see Appendix, Supplementary Figure S1). The two groups were comparable in terms of demographic characteristics such as age, sex, and socioeconomic status and baseline disease characteristics such as number of previous nebulization, proportion of children having other atopies, and family history of asthma (see Appendix, Supplementary Table S1).

The median duration of symptoms was 24 hours in both groups. The baseline PRAM score at the time of presentation was 5 with interquartile range of 4 to 6 in both the groups. Hence, both the groups are comparable in terms of duration and severity of the current asthma exacerbation. PRAM scores were assessed at hourly intervals until 4 hours after intervention and were compared between the two groups. The difference observed between the groups was assessed by Mann–Whitney U-test and was statistically insignificant (Table 1). Four hours after intervention, only three children in group A (4.7%) and two children in group B (3.1%) continued to have a PRAM score of 4 to 7 (moderate severity). This difference was found to be statistically insignificant with a P value of 0.1. The mean PRAM scores with standard error have also been provided as a bar graph with error bars (Figure 1).

Table 1.

Hourly PRAM scores for the first 4 h after intervention

Time period of assessment	Group A (N=64) (1 mg/kg/day)	Group B (N=64) (2 mg/kg/day)	Statistical significance (P value*)
	Median (IQR)	Median (IQR)
PRAM score at 1 h	4 (4–4)	4 (4–4.75)	0.94
PRAM score at 2 h	4 (2.25–4)	4 (2.25–4.0)	0.68
PRAM score at 3 h	1 (0–3)	2 (0–3)	0.35
PRAM score at 4 h	0 (0–0)	0 (0–0.75)	0.29

IQR Interquartile range; PRAM Pediatric Respiratory Assessment Measure.

*Mann Whitney U test.

Figure 1.

Mean hourly Pediatric Respiratory Assessment Measure (PRAM) scores with standard error in the first 4 h after intervention.

In group A, three children were admitted, out of which two children received magnesium sulphate infusion and subsequently required subcutaneous Terbutaline. In group B, two children were admitted and subsequently one child required magnesium sulphate infusion, whereas the other child had improved with continued salbutamol nebulization and oral steroids administered as per the study protocol. None of the children from either group required aminophylline infusion or mechanical ventilation or paediatric intensive care unit (PICU) transfer (Table 2). Four children in group A (6.3%) and three in group B (4.7%) had abdominal pain. This difference was statistically insignificant. In our study, vomiting reported by the parents was the predominant complaint in both the groups with 7 (11%) children in group A and 16 (25%) in group B and the difference was statistically significant. The risk of vomiting was 2.28 times higher in group B compared to group A (see Appendix, Supplementary Table S2).

Table 2.

Secondary outcomes

	Group A (1 mg/kg/day) (N=64)	Group B (2 mg/kg/day) (N=64)	Statistical significance (P value*)
Children requiring hospital admission, n (%)	3 (4.7%)	2 (3.1%)	1.0
Children requiring magnesium sulphate infusion, n (%)	2 (3.1%)	1 (1.6%)	1.0
Children requiring Terbutaline injection, n (%)	2 (3.1%)	0	0.49
Time for symptom resolution in hours, median (IQR)	24 (20–30)	24 (20–24)	0.52
Recurrence of wheeze, n (%)	5 (7.8%)	3 (4.7%)	0.71

IQR Interquartile range.

*P value was checked using Fischer’s exact test for categorical data and Mann Whitney U test for continuous data.

DISCUSSION

This study was undertaken to compare the clinical outcome and side effect profile of oral prednisolone administered as either 1 mg/kg/day or 2 mg/kg/day for acute moderate exacerbation of asthma in the preschool age group (1 to 5 years). Previous studies done on the paediatric population had evaluated children in the age group of 2 to 15 years. It is known that the clinical profile, response to steroids, and side effects expected from steroid course are not uniform across different age groups. Hence, our study is unique and different from the previous ones as we had included only the children belonging to the preschool age group (1 to 5 years old).

Though other steroids such as dexamethasone had shown promising results in the treatment of exacerbation, prednisolone was used in our study because our hospital provides it free of cost to all patients. Prednisolone is also cheaper and remains the most used steroid in clinical practice for treating an asthma exacerbation (10). For the assessment of severity of asthma, we chose PRAM score because it had been shown that it reflects the changes in airway resistance closely, has good internal consistency, and less inter-rater variability compared to other available scales (11).

In our study, we found that 30% to 35% of children had features of other atopic disease such as atopic eczema or allergic rhinitis. Also, 22% to 31% of children had family history of atopy in our study which was different from the findings by Langton et al., where 80% to 90% of the children in their enrolled population had family history of atopy (12). Possible recall bias or a comparatively higher proportion of our study children being episodic wheezers could have contributed to this difference in the observation and was not found to be significant after adjustment.

The main clinical outcome assessed in our study was the difference in PRAM scores evaluated over certain predetermined timeframes. We also evaluated the time taken for resolution of symptoms, recurrence of wheeze attack, requirement of escalation of therapy, and hospital admission rates. The median PRAM scores measured at 1-, 2-, 3- and 4-hour duration after the intervention were compared between the two groups and these differences were found to be statistically insignificant. The time taken for resolution of symptoms and number of salbutamol nebulization required were analyzed and were found to be comparable too. Three children from group A and two children from group B required hospital admission out of which two from group A and one child from group B required escalation of treatment with magnesium sulphate infusion. The decision for admission and escalation of treatment was taken by the treating physician. In our study, recurrence of wheeze was found to be 8% with low-dose and 5% with high-dose prednisolone. In a previous study conducted with a different dosage regimen of 2 mg/kg stat followed by 1 mg/kg/day for 4 days, the recurrence rate was observed to be 7% (10). Hence, it is evident that there is no clear benefit of using high-dose steroid for exacerbations.

In an randomized controlled trial (RCT) done by Langton et al. among 98 children, it was found that steroid doses of 0.5 mg/kg/day, 1.0 mg/kg/day, and 2.0 mg/kg/day had similar outcomes when used in exacerbations (12). They had used pulmonary function tests to objectively document the severity of airway obstruction. The outcomes with regards to steroid dose of their study were similar to that of our study. Pulmonary function tests could not be done in our study due to nonavailability of specialized equipment like impulse oscillometry at our hospital.

One of the concerns with the usage of steroids is the potential to cause side effects. In our study, we observed that 2 mg/kg/day of prednisolone was associated with a higher rate of vomiting (25%) compared to that of 1 mg/kg/day of prednisolone (11%). This difference was statistically significant. Although previous studies found vomiting in 4.4% of children treated with prednisolone, the dose of steroid used and age group enrolled were different from that of our study (13). None of the parents from either group reported any behavioural problem in their children. However, in an RCT conducted by Kayani et al. in 86 children aged 2 to 16 years, a higher incidence of anxiety, aggressive behaviour, and hyperactivity was observed in the group which received a dose of 2 mg/kg/day compared to those who received 1 mg/kg/day of prednisolone (8). There was no specific mention about vomiting as a side effect in that study. The children enrolled in our study were comparatively younger than those who were enrolled in Kayani et al.’s study, which could explain the difference between the observations. Similar side effects were observed in a meta-analysis of 38 studies conducted by Aljebab et al.; however, the choice of steroid was not limited to prednisolone alone and other steroids had also been used in a few studies included in that meta-analysis (7).

Thus, we conclude that there were no significant differences in terms of clinical improvement between the 1 mg/kg/day and 2 mg/kg/day prednisolone dose when used for the treatment of acute moderate exacerbation of asthma in preschool children. In addition, a higher incidence of vomiting has been noted when prednisolone was used at a dose of 2 mg/kg/day compared to that of 1 mg/kg/day.

Author Contributions: PKB and VC planned the study. PKB carried out the study under supervision from VC. PKB was involved in data collection. KTH and VC were involved in data analysis. The first draft was written by PKB and was revised with inputs from VC and KTH. All authors have seen and approved the final draft.

Funding: There are no funders to report for this submission.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.