3 Evidence

NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.

Clinical evidence

The main clinical evidence comprises 21 studies

3.1 The EAC assessed 21 full text comparative studies. Twelve were randomised controlled trials, 2 cross-over studies, 5 retrospective studies, 1 prospective study, and 1 study collected data prospectively for the Sedaconda ACD‑S arm but used retrospective data for the intravenous arm. Fifteen abstracts identified were not included in the evidence review. The EAC focused on primary studies only and did not extract data from 1 meta-analysis to avoid duplication of data. There was no published evidence on using Sedaconda ACD‑S in children.

3.2 All included studies were peer‑reviewed, and none were done in the UK. The included studies covered 6 population groups:

  • people after cardiac surgery (8 studies, 798 people)

  • people after cardiac arrest having therapeutic temperature management (3 studies, 816 people)

  • people with acute respiratory distress syndrome (2 studies, 88 people)

  • people with various surgical indications (2 studies, 270 people)

  • people having head and neck surgery who need a tracheostomy (1 study, 29 people)

  • people with pulmonary disorders (1 study, 30 people)

  • people with over 12 hour (1 study, 40 people) and 24‑hour sedation needs (2 studies, 361 people).

    For full details of the clinical evidence, see section 3 of the assessment report in the supporting documentation on the NICE website.

Clinical experts identified 3 particularly important clinical outcomes

3.3 The EAC, after consultation with clinical experts, identified 3 outcomes of particular clinical importance: time on mechanical ventilation, wake‑up time and sedation efficiency. Other outcomes reported across the 21 included studies were: intensive care and hospital length of stay; cognitive and neurological status; cardiac, renal and hepatic markers and blood gas results.

Evidence shows that inhaled sedation using Sedaconda ACD-S leads to faster wake-up time and maintains adequate sedation, but time on mechanical ventilation is uncertain

3.4 Wake‑up time, usually reported as extubation time (the time from stopping the sedative infusion to taking out the endotracheal tube), was measured in 6 studies and found to be significantly shorter in the volatile sedation arms compared with the intravenous arms across all the heterogeneous populations. The EAC concluded that sedation given using Sedaconda ACD‑S offers benefit over intravenous sedation in terms of wake‑up time. This is likely attributed to using the volatile sedatives that Sedaconda ACD‑S allows to be used rather than the device itself.

3.5 Inhaled sedation using isoflurane delivered with Sedaconda ACD‑S was non-inferior to propofol in maintaining adequate sedation (time spent at the desired sedation depth) without rescue medications in a large randomised clinical trial (n=301; Meiser 2021).

3.6 Eleven publications reported time on mechanical ventilation. The difference in time on mechanical ventilation between the volatile arms and the intravenous arms was uncertain because only 3 studies reported statistically significant differences (matched analysis of Krannich [2017], Rohm [2008] and Rohm [2009]) and the rest of the studies found non‑significant differences in time on ventilation.

There is uncertainty in the evidence on length of stay for inhaled sedation and intravenous sedation

3.7 All included studies were inconclusive about the measured outcomes for length of stay. The studies looked at different sedative drug combinations, and any differences between groups are likely to be because of these drug differences as well as the variables involved in patient treatment and could not be solely attributed to using the device.

Evidence is inconclusive for other outcomes that benefit patients

3.8 Eight publications reported on cognitive and neurological outcomes, 9 studies reported on cardiac, renal and hepatic biochemical markers and 6 studies reported on patient blood gas results. Most of the studies were not statistically significant in lowering the incidence of delirium, lowering organ‑specific biomarkers and improving oxygenation compared with intravenous sedatives.

Cost evidence

The company's cost analysis model compares inhaled sedation using the Sedaconda ACD-S device with intravenous sedation

3.9 The company's cost model compared inhaled isoflurane with intravenous propofol. The cost model had a 30‑day time horizon and included adult patients needing mechanical ventilation for 24 hours or longer in intensive care. The clinical input parameters included the mean body weight of people having sedation in intensive care, the time on mechanical ventilation (mean, in days) and the length of stay in intensive care (mean, in days). The company also submitted a scenario analysis that compared inhaled isoflurane with intravenous midazolam. The EAC adapted this analysis to extrapolate the cost analysis in children. The EAC inputted an average body weight of 12 kg for a child but did not change the other clinical parameters. For full details of the cost evidence, see section 4 of the assessment report in the supporting documentation on the NICE website.

Sedaconda ACD-S device remains cost saving in the EAC's updated model

3.10 The EAC agreed with the company's cost model overall. The EAC noted that the time on mechanical ventilation and the length of stay in intensive care were based on the results of a post-hoc analysis done in a subset of people (n=177) from the original randomised clinical trial (n=301; Meiser 2021). This subgroup consisted of people that did not have their sedation approach switched after the 48‑hour randomisation period. The EAC corrected some costs, added the cost of training for switching from intravenous to inhaled sedation and found that Sedaconda ACD‑S remained cost saving by £3,833.76 per adult.

The company cost analysis results are robust but there is uncertainty around the clinical inputs that drive cost savings

3.11 Sensitivity analysis indicated that the cost analysis was robust to changes to drug doses, drug costs and to the addition of training costs with Sedaconda ACD‑S. The EAC threshold analysis showed that, if time on mechanical ventilation is the same for both methods of sedation, inhaled sedation using Sedaconda ACD‑S was cost saving compared with intravenous propofol when the duration of intensive care stay is reduced by 1.5 days. However, the length of stay in intensive care and time on mechanical ventilation were sourced from the post-hoc analysis in a subset of study patients from Meiser (2021). These outcomes were not the primary outcomes of the trial and they were not included in the publication.

Exploratory analysis suggests that inhaled sedation with Sedaconda ACD-S is cost saving in children

3.12 The EAC used the cost analysis model comparing inhaled isoflurane with intravenous midazolam to explore the economic impact of using inhaled sedation in children. Clinical parameters were informed from Krannich (2017). The cost analysis estimated a cost saving of £2,837.41 per child. The clinical experts considered it reasonable to assume that children have a similar response to intervention to adults.

  • National Institute for Health and Care Excellence (NICE)