Results: step-up randomised controlled trial

Sites and patients

Site selection and set-up

Expressions of interest and completed site feasibility questionnaires were received from 26 potential sites across England, Wales and Scotland. All sites were invited to take part in the trial, of which two were ultimately not able to progress with set-up (one due to research capacity issues and one due to equipoise issues).

In total, 24 sites, covering 25 critical care units, recruited patients into the FIRST-ABC step-up RCT. The first sites opened in August 2019, on schedule, and the final site opened in July 2021. By the end of the internal pilot, 22 sites were open to recruitment. The characteristics of the sites are shown in Table 4.

In relation to research governance, the median time from provision of the final local information pack to the issuing of local confirmation of capacity and capability was 46 (IQR 29.5–99.5) days. The median time from local confirmation of capacity and capability to the start of patient screening at sites was 13 (IQR 4–26) days. The median time from the start of patient screening to the first patient recruited at sites was 11 (IQR 2–42) days. In total, the process from provision of the final local information pack to first patient recruited took a median of 113 (IQR 64–142) days.

Of the 22 sites that were open prior to the COVID-19 outbreak, 18 formally paused recruitment at least once due to the impact of COVID-19 on clinical and research activity. The majority of these sites paused in March 2020 due to the COVID-19 first wave, and most had reopened to recruitment by September 2020. Two additional sites were opened after the initial COVID-19 period in order to mitigate some resultant impact on the trial timeline. Overall, two sites formally closed ahead of the completion of recruitment – with all other sites remaining open until the end of the recruitment period. In total, each site participated in the step-up RCT for a median (IQR) of 19.4 (17.1–22.3) months.

Patient screening, randomisation and consent

Between August 2019 and November 2021, 18,976 patients were admitted to participating PICU/HDUs and screened for inclusion in the step-up RCT, from which 3825 were deemed to meet inclusion criteria (Figure 3). Of those not meeting inclusion criteria (n = 15,151), most did not require NRS for an acute illness (n = 15,026, 99.2%).

FIGURE 3 Consolidated Standards of Reporting Trials flow of screening, randomisation and follow-up through the step-up RCT. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

Of patients meeting inclusion criteria, 2376 additionally met exclusion criteria and were not eligible for the trial. The most common reasons for exclusion were prior receipt of HFNC or CPAP for > 2 hours in the prior 24 hours (n = 1085, 45.7%); receipt of home non-invasive ventilation prior to admission (n = 509, 21.4%); and a clinical decision to commence a form of NRS other than HFNC or CPAP (n = 393, 16.5%).

Of the remaining 1449 eligible patients, 600 (41.4%) were randomised into the trial and 849 (58.6%) were not. The most common reasons for eligible patients not being enrolled in the trial were that patients were either missed or identified too late for recruitment (n = 438, 51.6%) or a clinical decision was made not to enrol the patient (n = 325, 38.3%). The full sample was recruited 2 months ahead of the schedule (Figure 4). The overall site recruitment rate was 1.7 patients per month with a median recruitment rate of 1.1 (IQR 0.3–1.8) patients across sites.

FIGURE 4 Step-up RCT – actual vs. anticipated patient randomisation. Comparison of actual vs. anticipated cumulative randomisation of patients into the FIRST-ABC step-up RCT. During the first wave of the COVID-19 epidemic in the UK, 17 (of 24) sites suspended recruitment for an average of 4.8 months. During the second wave, five sites suspended recruitment for an average of 2.6 months. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

Among the 600 enrolled, 301 were randomised to the HFNC group and 299 to the CPAP group. After accounting for complete withdrawals, 300 in the HFNC group and 295 in the CPAP group formed the ITT population. In the HFNC group, 295 started respiratory support following randomisation compared with 278 in the CPAP group, forming the primary analysis set. Of those randomised to HFNC, 290 started HFNC, while 246 in the CPAP group started CPAP as randomised, forming the per-protocol population (see Appendix 4).

In the primary analysis set, the primary outcome was observed in 264 in the HFNC group and in 281 in the CPAP group, with 14 censored in each group. In the per-protocol population, the primary outcome was observed in 275 in the HFNC group and in 236 in the CPAP group.

Baseline characteristics

The randomised groups had similar characteristics at baseline (Table 5). In the primary analysis set, the median (IQR) age in months was 10 (2–31) and 9 (1–27) in the HFNC and CPAP groups, respectively. Just under 40% were female in both groups and around half had at least one comorbidity (HFNC: 48.5%, CPAP: 46.2%).

Overall, the main reasons for admission to critical care were either bronchiolitis (HFNC: 48.5%, CPAP: 49.8%) or another respiratory condition (HFNC: 18.6%, CPAP: 20.6%). At the time of randomisation, most patients were in moderate respiratory distress (HFNC: 57.4%, CPAP: 59.9%), with similar oxygen requirements [median (IQR) fraction of inspired oxygen, HFNC: 0.30 (0.21–0.48), CPAP: 0.30 (0.21–0.44)].

Baseline characteristics were similar in the per-protocol population and are shown in Table 6. The baseline characteristics of the full ITT population (i.e. including the small number of patients who did not start any respiratory support following randomisation) are shown in Appendix 5.

Clinical management

In both groups, the randomised treatment was started in the majority of children who started respiratory support [HFNC: 290/295 (98.3%), CPAP: 246/278 (88.5%)] - see Figure 7. A variety of devices and interfaces were used to delivery HFNC and CPAP (see Appendix 6).

Initiation of HFNC was quicker than was the initiation of CPAP (median 25.0 vs. 55.5 minutes) (Table 7). Adherence to the trial algorithms was good, with most patients receiving HFNC at the prescribed gas flow rates (Figure 5) and CPAP at the specified pressure level (Figure 6).

FIGURE 5 Step-up RCT – HFNC flow rates during the first 6 hours of treatment. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

FIGURE 6 Step-up RCT – CPAP pressures during the first 6 hours of treatment. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

More patients (109/246, 44.3%) in the CPAP group switched to HFNC than patients in the HFNC group switched to CPAP (74/290, 25.5%) (Figure 10 and Table 7). Patients in the CPAP group primarily switched for patient discomfort reasons, whereas patients in the HFNC group primarily switched due to severe respiratory distress (see Appendix 7).

FIGURE 7 Step-up RCT – clinical management of trial patients. a, Time to liberation was censored in five patients started on HFNC and four patients started on CPAP. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

Clinical effectiveness

Primary outcome

The median time from randomisation to liberation from respiratory support was 52.9 hours (95% CI 46.0 to 60.9 hours) in the HFNC group and 47.9 hours (95% CI 40.5 to 55.7 hours) in the CPAP group [absolute difference 5.0 hours (95% CI −10.1 to 17.4 hours); adjusted HR 1.03, one-sided 97.5% CI 0.86 to ∞] (Figure 8). The bound of the one-sided 97.5% CI fell within the prespecified non-inferiority margin. Results were similar in the per-protocol analysis (adjusted HR, HR 1.03, 95% CI 0.86 to 1.23) (Table 8; Figure 9). Proportional hazards assumptions were checked by examining plots of −ln[−ln(survival)] over time and scaled Schoenfeld residuals from each Cox proportional hazards model. No evidence of departures from proportional hazards was observed.

FIGURE 8 Step-up RCT – time to liberation from respiratory support in the primary analysis set. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

FIGURE 9 Time to liberation from respiratory support in the per-protocol population. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

The time to liberation according to whether treatment failure occurred is shown in Appendix 8. Patients experiencing treatment failure had a much longer median (IQR) time to liberation than did patients without treatment failure – more so for the HFNC group compared to the CPAP group [79.8 (48.0–146.8) vs. 56.0 (26.1–134.0)].

FIGURE 10 Step-up RCT – respiratory support treatments provided overtime to children in the primary analysis set. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

Subgroup analyses

In prespecified subgroup analyses, there was a significant difference in treatment effect between patients who were receiving respiratory support at randomisation, in whom CPAP was more effective, and those who were not, in whom CPAP was less effective (Figure 11). There was no significant heterogeneity across other patient subgroups.

FIGURE 11 Step-up RCT – subgroup analysis of the primary outcome of liberation from respiratory support in the primary analysis set. Median (IQR) observation time. Primary analysis set: HFNC 50.0 hours (25.5, 96.6), CPAP 44.8 hours (24.3, 92.9). Per-protocol analysis: HFNC 49.9 hours (25.4, 95.8), CPAP 44.7 hours (24.3, 90.0). Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

Secondary outcomes

There was no significant difference in the rate of intubation by 48 hours, with 15.4% intubated in the HFNC group and 15.9% in the CPAP group (adjusted OR 0.99, 95% CI 0.61 to 1.62), but there was a significant difference in the use of sedation while receiving HFNC or CPAP – with less sedation use in the HFNC group (27.7% vs. 37.0%), equating to an adjusted OR of 0.59 (95% CI 0.39 to 0.88). The durations of critical care unit and acute hospital stay were shorter in the HFNC group compared with the CPAP group [mean (SD) acute hospital stay: 13.8 (26.8) for HFNC and 19.5 (47.7) for CPAP]. COMFORT-B scores were similar between the groups, as was the level of parental stress at/around the time of consent.

Adverse events

The number of participants with one or more AEs was low in both groups, occurring in 17 out of 295 (5.8%) in the HFNC group and in 30 out of 278 (10.8%) in the CPAP group (Table 9). A total of four SAEs were reported – all were cardiac arrests, one in the HFNC group and three in the CPAP group.

Sensitivity analyses

Planned and post hoc sensitivity analyses did not alter interpretation of the primary outcome (see Appendix 9). When repeating the primary analysis in the full ITT population (assigning a nominal 2 hours of respiratory support to patients who did not start any respiratory support following randomisation), the adjusted HR was 0.98 (95% CI 0.83 to 1.16) (Figure 12).

FIGURE 12 Step-up RCT – time to liberation from respiratory support – post hoc sensitivity analysis in all randomised children including those who were not started on respiratory support. To enable the inclusion of all randomised patients we assigned a minimal time to liberation of 2 hours in those who did not start any respiratory support following randomisation, and repeated the primary analysis. Reproduced with permission from Ramnarayan et al.31 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

Cost-effectiveness analysis

Resource use and costs up to 6 months

Resource use up to 6 months post randomisation is reported in Table 10. Patients in the HFNC group had, on average, shorter stays in paediatric critical care units (5.08 vs. 7.05 days) and in the general medical ward (9.04 vs. 9.74 days) during the index hospital admission compared to patients in the CPAP group. A larger number of patients in the HFNC group were re-admitted into hospital during the 6 months following ultimate discharge from the index hospital admission compared to the CPAP group (7.80 vs. 6.75% of patients had at least one admission to critical care, 38% vs. 36% had at least one admission to the general ward). The average duration of critical care unit stays during re-admissions was similar between randomised groups (1.15 vs. 1.24 days), but HFNC patients had slightly longer stays in the general medical ward compared to the CPAP group (4.45 vs. 3.65 days). The mean total length of stay up to 6 months was lower in the HFNC group compared to CPAP (19.71 vs. 21.68 days).

The number of outpatient visits and use of community healthcare services following discharge from hospital up to 6 months for HFNC and CPAP patient groups was derived from responses to the HSQ and is summarised in Appendix 10. Patients in the HFNC group had, on average, more contacts with their general practitioner (GP), nurse, health visitor and counsellor services than patients in the CPAP group, but fewer number of outpatient visits and contacts with dietitian, occupational therapy, psychiatric nurse and physiotherapy services. Use of other community care services up to 6 months was low and similar between the two groups.

Total costs (GB£)

Mean total costs per patient at 6 months post randomisation are reported in Table 11. The index hospital admission costs were the main driver of the total cost associated with the provision of HFNC and CPAP in this population, accounting for up to 74% and 81%, respectively, of the total costs at 6 months. Within the index admission, the cost of stays in critical care units was lower in the HFNC group compared to CPAP (£8658 vs. £12,584), and higher than those of stays in general medical wards for both groups. The re-admission costs were higher in the HFNC group than in the CPAP group. In re-admissions, the costs of stays in general medical wards were higher than the costs of stays in critical care units for both randomised groups. The costs of outpatient visits and community healthcare services were larger in the HFNC group than in the CPAP group (£418 vs. £355). The mean total costs per patient were lower in the HFNC group (£20,335) compared to the CPAP group (£24,142).

Health-related quality of life

Table 12 reports HRQoL for respondents of the follow-up questionnaires in the HFNC and CPAP groups at 6 months. The mean overall scores across the four PedsQL dimensions were similar between HFNC and CPAP patients (70 vs. 73 in the physical dimension, 71 vs. 68 in the emotional dimension, 81 vs. 81 in the social dimension, and 65 vs. 67 in the school functioning dimension). The mean total PedsQL score at 6 months were high in both randomised groups (71 and 72 in HFNC and CPAP group, respectively).

The mapped CHU-9D utility scores at 6 months were similar between the randomised groups (Table 13). At 6 months, HFNC compared to CPAP group had slightly lower life-years. The resultant mean QALYs at 6 months were slightly lower in the HFNC group.

Cost-effectiveness

The unadjusted incremental cost of HFNC compared to CPAC was −£3807, and this estimate was surrounded by a wide 95% CI that included zero (Table 14). After adjustment for baseline characteristics, the estimated incremental cost of HFNC compared to CPAP was −£5702, but the 95% CI around it was wide. The incremental life-years and QALYs of HFNC versus CPAP were found to be negative in both the unadjusted and adjusted analysis, but the magnitudes were small in all cases with 95% CIs including zero. The cost-effectiveness plane shows that the majority of points representing incremental costs and incremental QALYs fall in the third quadrant (south-west) of the cost-effectiveness plane, indicating that HFNC resulted in lower QALYs and lower costs, albeit with wide uncertainty (Figure 13). The INB for HFNC versus CPAP was positive, but there is statistical uncertainty around the INB; at £20,000 per QALY, the INB from adjusted analysis was £5628 (95% CI −£8 to £11,264).

FIGURE 13 Step-up RCT – uncertainty in the mean costs (GB£) and QALY differences and their distribution for HFNC vs. CPAP (within 6 months post randomisation). (Figure not reproduced here; see the original article.)

FIGURE 14 Screening, randomisation and follow-up through the step-down RCT. a, Numbers meeting individual exclusion criteria do not add to the total as some patients met > 1 criterion. b, In the HFNC group, time to liberation was censored for 23 patients: 4 refused retrospective consent, 8 died prior to liberation from respiratory support, 10 were discharged from critical care on respiratory support and data are unavailable, 1 patient was transferred to another critical care unit on respiratory support and data are unavailable. c, In the CPAP group, time to liberation was censored for 12 patients: 6 refused retrospective consent, 3 died prior to liberation from respiratory support, 2 were discharged from critical care on respiratory support and data are unavailable, 1 patient was transferred to another critical care unit on respiratory support and data are unavailable. Reproduced with permission from Ramnarayan et al.32 Copyright © 2022 JAMA. All rights reserved. (Figure not reproduced here; see the original article.)

The results of the subgroup analysis are reported in Report Supplementary Material 3. Estimated INBs were similar across all subgroups, except for the subgroup of patients who were admitted due to cardiac reasons. The INB for the cardiac patient subgroup is large relative to all other subgroups. For all other subgroups, as for the overall results, the 95% CIs around the INB included zero.

Report Supplementary Material 4 reports the mean with 95% CI of the INB (at £20,000 per QALY gain) according to alternative assumptions, compared with the base case. The INBs from alternative scenarios are similar to the base-case INB (£5628), with overlapping CIs, suggesting that that the base-case results were robust to the main assumptions made in the base case.