For the primary analysis of preterm infants treated following ventilation, there were no statistically significant differences in the primary outcome reported in the studies comparing HHHFNC and NCPAP that were included in the clinical review. The only difference identified was related to the rate of adverse events, notably in nasal injury in favour of HHHFNC. No long-term adverse events from nasal injury were identified from the studies included in the clinical review.
Given the absence of any differences in primary outcome or in long-term adverse events, the time horizon of the economic model was limited to the period during which a preterm infant received oxygen therapy. With the only difference in outcome being short-term nasal injury, this can be the only difference in quality of life for the patient.
Utility value derivation from preterm infants cannot be done directly and in this case would likely result in only very small quality-of-life decrements related to skin irritation and infection. Treatment is rapidly administered, and from the clinical experience of the authors who are clinicians (BS, PS) any irritation clears normally in 5–7 days. As such, any utility loss was thought to be so small as to be inconsequential to include in the analysis, although the treatment costs of this adverse event could be included. In the clinical experience of the authors who are clinicians (BS and PS), nasal trauma from NCPAP can be so severe as to require plastic surgery. As this event was thought to be very rare and there was no evidence in the available literature of this event occurring, it has not been included in the analysis.
Given the absence of any difference in primary outcome and utility between the technologies, a cost–utility analysis could not be undertaken.
In addition, in the absence of differences in primary outcome the only cost-effectiveness analysis that could be undertaken would be based on the use of secondary outcome data; in this case, the incremental cost-effectiveness ratio would be defined as the cost per case of nasal injury avoided. As this is not a primary outcome in any of the studies included in the clinical effectiveness review, in our opinion it is unlikely that such an analysis would be meaningful and so cost-effectiveness analysis was not undertaken based on any secondary outcome.
Given the inability to undertake cost–utility analysis or meaningful cost-effectiveness analysis, coupled with there being evidence for no statistically significant difference between treatment arms for the primary clinical outcome, the need for intubation, a cost-minimisation analysis for the primary analysis was undertaken comparing HHHFNC with NCPAP from the perspective of the NHS. For the secondary analysis of infants who had received no prior ventilation, there was an absence of evidence on the difference in the primary outcome, the need for intubation; only one completed small study52 examined this outcome whereas another, which was halted early,33 investigated a similar outcome (respiratory failure; which was a composite end point) and both compared HHHFNC with different devices (NIPPV52 and NCPAP33) and so we considered there to be an absence of evidence (as opposed to evidence of no difference from a meta-analysis for the primary outcome). Thus, while considered for the secondary analysis, a cost-minimisation analysis was potentially misleading, as it could lead decision-makers towards a cheaper technology which has unknown relative effectiveness.
Treatment resource use and costs
Resource use of treatment included capital equipment, consumable costs and clinician time taken to establish a preterm infant onto either HHHFNC or NCPAP. All prices are in 2015 GBP unless otherwise stated. Given the time horizon is the period up to discontinuation of NCPAP or HHHFNC, no discounting needed to be applied to costs.
Clinician time
From the clinical experience of two of the review authors (BS and PS), there is no difference in the time taken to set up a preterm infant on HHHFNC or on NCPAP and so this was not included in the analysis.
Capital equipment
Nasal continuous positive airway pressure can be delivered either through mechanical ventilators or through dedicated NCPAP equipment. It is the opinion of the authors who are clinicians (BS, PS) that the preference is to use dedicated NCPAP equipment, as this equipment is supposed to provide a nasal airflow that is more suitable for NCPAP than mechanical ventilation. In addition, the use of dedicated NCPAP equipment means that mechanical ventilators can be kept free for use elsewhere. Dedicated NCPAP equipment was therefore included as a resource in the evaluation rather than mechanical ventilators.
It is the opinion of the authors who are clinicians (BS and PS) that not only is there a range of manufacturers with different devices that can be used, the prices quoted by the manufacturer can vary depending on the volume purchased.
From NHS Supply Chain48 information the quoted price for a non-humidified NCPAP machine (the Maxblend NCPAP flow generator complete system by Armstrong Medical Ltd, Coleraine, Northern Ireland) was £6122. Although there may be other devices available, this appeared to be the only fixed (rather than portable) system that can be used specifically on preterm infants on NHS Supply Chain.48 This compares with clinical experience of one the authors (BS) on the cost of a NCPAP machine being in the region of £5000 depending on make and volume purchased. As such, the £6122 figure for the Maxblend NCPAP machine seemed reasonable and was used in the analysis.
For HHHFNC, again there are several machines on the market that could potentially be used to deliver care. The Optiflow 850™ (Fisher & Paykel, Auckland, New Zealand) is used in the neonatal unit where one of the authors (BS) is based. The NHS Supply Chain48 cost of this device is £2755 and this figure was used in the economic analysis.
To provide a unit cost per infant of each machine, we have assumed that each machine lasts 5 years and that any service costs for machines are equal and so do not need to be included in analysis. We have then assumed that the devices are in use for 80% of the time and that each preterm infant requires oxygen support for 43.5 days, which is the mid-point of the medians for HHHFNC and NCPAP reported in Manley et al.38
Putting these assumptions into a calculation suggests the unit cost of each machine per infant supported is equal to:
the cost of the machine (£6122 for NCPAP and £2755 for HHHFNC)
divided by 80% (the machine utilisation rate)
divided by 365.2 × 5 (the number of days in the 5-year lifespan on the machines)
multiplied by 43.5 (the number of days, on average, an infant requires use of NCPAP or HHHFNC).
This suggests a unit cost of £182 per preterm infant for a NCPAP machine and £82 per preterm infant for a HHHFNC machine.
Consumables
As was the case for capital equipment, there are a range of suppliers and potential prices available from the NHS Supply Chain48 for NCPAP and HHHFNC consumables (i.e. equipment that is required as part of the treatment but which is disposed of and cannot be reused, such as nasal canulae or tubing).
Given the variation in potential prices for different systems and the potential difference in quoted prices and prices paid, the weekly cost of consumables used in the economic analysis was provided directly by the neonatal unit that had provided information on the NCPAP and HHHFNC capital equipment (where BS is based). This approach was undertaken to ensure consistency and that any difference in the cost of consumables was that which was really experienced in a NHS setting.
For HHHFNC the total cost of all consumables was estimated to be £67 per week and for NCPAP it was estimated to be £55 per week.
Adverse events
The only evidence showing a statistically significant difference in the incidence of adverse events between infants on HHHFNC and NCPAP was nasal injury. There were no cases of nasal injury that were serious enough to require corrective surgery described in any of the studies included in the clinical review.
Based on the experience of two of the review’s authors who are clinicians (BS and PS), the majority, if not all, nasal injury would be relatively minor with no long-term consequences. One author was unaware of damage that had led to corrective surgery whereas another could think of only one case in 5 years in which nasal damage had resulted in the requirement for corrective surgery. Although it is recognised that there can be long-term aesthetic consequences from nasal injury, we are not aware of this as an issue nor are we aware of any literature that may point to this. As such, occurrences of serious and long-term nasal injury from either HHHFNC or NCPAP were not considered in the economic analysis, although the potential for long-term consequences from nasal injury should be considered as part of the overall analysis of the two technologies.
Treatment for nasal injury while the preterm infant is on oxygen therapy was described as being antiseptic/antibacterial cream two or three times a day for 5–7 days if it is ulcerated with rest to the infant’s septum.
As the preterm infant will be in a high-dependency care unit, Royal College of Nursing standards state a staff ratio of one nurse to two preterm infants will be required.56 From a nurse time perspective, it is likely that application of the cream would form part of the care routine for a preterm infant and there is no real opportunity cost of the time taken to apply the cream, as the nurse would have to be on the unit in any event. As such, including the small amount of time it would take to apply the cream by a nurse is, in our opinion, not appropriate. The cost also of the antiseptic cream applied could vary by the preparation. It is assumed that the cream would contain chlorhexidine. Such creams are inexpensive even if bought privately. For example, 15 g of neomycin 0.5% chlorhexidine hydrochloride 0.1% cream can be purchased for £2.85.57 With such low costs there is no need to be too precise when measuring the volume of cream used or on the exact cream used and price paid. As such, we have assumed that over the 5- to 7-day treatment period there is a £2 cost for the cream used.
Manley et al.38 and Collins et al.37 reported changes in treatment because of nasal injury. It is not clear whether or not changes in treatment protocol reflect routine clinical practice in the NHS. As a result of this, and as the changes in treatment did not result in longer lengths of stay (in Manley et al.38) or statistically significantly higher reintubation rates (in Manley et al.38 and Collins et al.37), changes in treatment because of nasal injury are not considered as being economically important.
Resource and cost summary
The costs per preterm infant for HHHFNC and NCPAP are summarised in . The data support the clinical opinion of the authors who are clinicians (BS and PS) that there is not likely to be a statistically significant difference between the costs of therapy. The higher capital equipment costs of NCPAP are not outweighed by the higher consumable costs of HHHFNC, with HHHFNC estimated to cost £26.37 less than NCPAP per preterm infant treated.
Costs per preterm infant for HHHFNC and NCPAP
Analysis of uncertainty
Ordinarily in an economic evaluation, scenario analysis and deterministic and probabilistic sensitivity analysis would be used to explore parameters when there was uncertainty in the economic model.
As we carried out a cost-minimisation analysis, this analysis has focused on the resources and costs associated with two treatments that the clinical evidence suggests are equally efficacious for the primary outcome of interest. The only notable difference between the treatments was in nasal injury as an adverse event and this has a very low cost per patient.
No distributions on any of the costs or resource use are available and so any probabilistic analysis of uncertainty is not possible. However, assumptions were made on the life expectancy of NCPAP and HHHFNC machines. As the cost saving for HHHFNC is driven by the greater capital cost of NCPAP, these assumptions were explored with sensitivity analysis.
shows the two-way sensitivity analysis of the cost differential with HHHFNC compared with NCPAP as the utilisation rates vary between 20% and 100% and the lifespan varies between 2 and 10 years.
Two-way sensitivity analysis of cost differential of NCPAP compared with HHHFNC as machine lifespan and utilisation rates vary
The threshold analysis shows that if the lifespan of the machines reaches 6.8 years then HHHFNC would no longer be cost saving compared with NCPAP. A machine lifespan above 6.8 years means that NCPAP becomes the less costly option.
Changes in machine lifespan and utilisation rate are positively related to the number of infants that can be used by each machine and therefore negatively related to the machine unit cost per infant (i.e. lower utilisation rates/machine lifespans lead to a lower number of infants that can use a machine over its lifespan, and therefore higher unit costs of the machine per infant). Although these changes in unit cost will be proportionally the same for each technology, the machine cost of NCPAP is higher than with HHHFNC. As such, the change in the absolute difference in unit cost per infant between the technologies is negatively related to the utilisation rate and machine lifespan (i.e. higher utilisation rates/machine lifespans lead to a smaller absolute difference in the machine unit costs per infant between NCPAP and HHHFNC).
It is also possible that different neonatal units pay different costs for consumables depending on the NCPAP and HHHFNC systems employed. However, what is important for our economic analysis is the size of the cost differential in consumables rather than the consumable costs per se. As costs can vary between units, a two-way sensitivity analysis was also undertaken to show how the differential in consumable costs together with the lifespan of the different machines change. The difference in consumable costs ± £24 (200%) is shown in ; in the initial analysis there is a cost difference of –£12 per week (consumable cost with NCPAP is £55 and with HHHFNC is £67).
Two-way sensitivity analysis of cost differential of NCPAP compared with HHHFNC
The results presented in demonstrate that the main finding of the economic analysis, that is HHHFNC is cost saving compared with NCPAP, is relatively sensitive to changes in the difference in weekly consumable costs of the two technologies. Assuming a 5-year lifespan for equipment as in the initial analysis, if the difference in consumable prices rises approximately by 35% from £12 to £16.24 then HHHFNC will no longer be cost saving compared with NCPAP.
