Observed: no improvement in survival without kidney failure; 28-day mortality was 34 more deaths per 1,000 with vasopressin, compatible with 54 fewer to 123 more. Observed secondary outcome: 99 fewer patients started renal-replacement therapy per 1,000, but this was clinician-decided and uncertain.

Neutral primary outcome; mortality confidence interval includes material benefit and harm. The renal-replacement result was secondary and does not justify routine first-line substitution.

CCR-modelled: vasopressin acquisition alone was approximately £303 to £505 per patient-day at the trial dose range using one 2025 local NHS formulary price. No trial-based UK cost-effectiveness or demonstrated ICU/hospital bed-day saving was available.

Not available: no trial-based NHS cost-effectiveness analysis. CCR-modelled: 1,000 patients each receiving 24 hours would require approximately £303,000 to £505,000 of vasopressin at the cited local price before offsets and delivery costs; duration and comparator-dose data are needed for a proper budget model. Not defensibly estimated: the eligible annual population and current early-vasopressin uptake are not established, and routine first-line use is likely uncommon.

• UK economic evaluation — Not available: No formal NHS cost-effectiveness analysis was reported. Do not monetise the secondary renal-replacement result without patient-level modality, duration and downstream-resource data.
• Illustrative NHS acquisition price — Observed: A 2025 local NHS formulary listed argipressin 20 units/1 mL at £101 per ampoule. This is an indicative local price, not a national procurement tariff.
• Drug, workforce and delivery requirement — CCR-modelled: At 0.03 to 0.06 units/minute, 24-hour use is 43.2 to 86.4 units, requiring approximately 3 to 5 whole 20-unit ampoules: about £303 to £505 per patient-day at the cited local price. This excludes any noradrenaline offset, central access/lumen, syringe pump, pharmacy preparation, nursing and ischaemia monitoring.

Public investment

£1,039,024.19 — NIHR Clinician Scientist Award; award NIHR/CS/009/007.

Funding scope

Verified NIHR award value; broader career/programme award attribution applies. Nominal awarded amount in the NIHR Funding and Awards record; no inflation adjustment. The award was a five-year Clinician Scientist Award centred on VANISH, so it should not be treated as a narrow per-paper cost. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.039 million award produced a 409-patient randomised trial across 18 UK adult ICUs and a mechanistic research programme. It showed no improvement in the primary kidney-failure-free-survival outcome with early vasopressin, while identifying a secondary reduction in renal-replacement therapy that requires cautious interpretation; this prevents an unsupported routine first-line switch to a substantially more expensive infusion.

VANISH strengthened a UK sepsis trial network and clarified that its early-substitution strategy is different from later adjunctive vasopressin use. Avoiding routine substitution also avoids extra ampoules, syringe-pump time, pharmacy preparation, line capacity and ischaemia monitoring; environmental consequences were not measured.

Keep noradrenaline as the default first-line agent and prevent protocol drift toward routine early substitution. Do not infer that VANISH rules out adjunctive vasopressin at escalating noradrenaline doses; that was not the tested strategy. If vasopressin is used, audit acquisition cost, pump/lumen use, digital ischaemia and renal-replacement initiation.

Observed: mortality estimates were imprecise and compatible with clinically important benefit or harm. Observed: renal-replacement initiation was a secondary, clinician-decided outcome and was not accompanied by a patient-centred renal benefit. Generalisability to adjunctive vasopressin practice is limited because the trial compared early first-line strategies.

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Observed: 220 fewer deaths per 1,000 at six months, but extra survivors spanned vegetative state, severe disability and better outcomes. At 24 months there were 205 fewer deaths per 1,000, with continuing shifts across disability categories.

Large mortality effect with a preference-sensitive disability distribution; the one-year NHS economic model was above the usual NICE threshold and highly sensitive to assumptions.

Published economic analysis: approximately £9,627 higher one-year cost per patient and an ICER of £96,155.67 per QALY; central estimate £9.627 million additional one-year cost per 1,000. The intervention creates theatre, neurosurgical, rehabilitation and long-term care demand.

Published economic analysis: decompression added £9,627.36 per patient over one year in the model. Calculated from the published point estimate: £9.627 million additional one-year NHS cost per 1,000 treated. This is not an annual cash requirement and should be scenario-modelled by neurological outcome and care setting. Not defensibly estimated: eligible refractory intracranial-hypertension volume should be derived from current trauma-network and neurocritical care data, not all severe traumatic brain injury.

• One-year NHS cost — Published economic analysis: Initial admission cost was £10,296 with decompression versus £4,221 with medical treatment, difference £6,075. One-year total was £16,034.36 versus £6,407.00, difference £9,627.36 per patient.
• QALYs and cost-effectiveness — Published economic analysis: One-year QALYs were 0.41 versus 0.31, incremental 0.10; ICER £96,155.67 per QALY and incremental net monetary benefit -£6,623.68 at £30,000/QALY.
• Capacity and long-term care sensitivity — Published economic analysis: Sensitivity analyses produced ICERs from £38,764.58 to £195,894.01 per QALY. The model used an annual cost of £70,491 for persistent vegetative state. It was a historical one-year model and did not fully value lifetime rehabilitation, care or caregiver burden.

Public investment

£1,182,546.17 — MRC–NIHR Efficacy and Mechanism Evaluation programme; award 09/800/16.

Funding scope

Verified MRC–NIHR award value. Nominal awarded amount in the NIHR Funding and Awards record; no inflation adjustment. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.183 million award supported an international 408-patient trial at 52 centres in 20 countries, subsequent 24-month follow-up and an NHS economic analysis. It established that last-tier decompressive craniectomy substantially reduces mortality but changes the distribution of survival with disability, replacing uncertainty with quantified information for treatment and shared decision-making.

The trial changed the evidence base used in severe traumatic brain injury recommendations and made long-term functional outcomes, rather than mortality alone, central to decisions. Implementation requires neurosurgical theatre, cranioplasty, rehabilitation and long-term care capacity; the one-year economic analysis showed material additional NHS cost and should not be interpreted as a simple bed-saving intervention.

Predefine last-tier eligibility, including sustained intracranial pressure above 25 mm Hg despite tiered treatment, and document timing; the operation should occur promptly once chosen. Use structured family discussion showing the full outcome distribution, not mortality alone, and elicit values regarding survival with dependency. Plan theatre, neurosurgical, cranioplasty, rehabilitation, neurodisability and community-care capacity; audit full Extended Glasgow Outcome Scale outcomes beyond discharge.

Unblinded treatment and substantial crossover complicate causal interpretation of treatment pathways. The benefit-harm balance is preference-sensitive because lower mortality is accompanied by more survivors with severe disability or vegetative state. Published economic analysis used a one-year horizon and historical assumptions; lifetime NHS, social-care and family costs remain uncertain.

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Observed: 90-day mortality was approximately 10 fewer deaths per 1,000, compatible with about 39 fewer to 20 more; shock resolved one day earlier by the median and about 47 fewer patients received a transfusion per 1,000.

Neutral mortality result with consistent physiological benefit; inexpensive generic treatment, but no demonstrated ICU or hospital bed-day saving.

CCR-modelled from the January 2026 Drug Tariff: a maximum seven-day 200 mg/day course is about £24 drug cost per patient, £24,052 per 1,000, before delivery and monitoring. Australian and New Zealand economic results found no clear value advantage and are not directly transferable to the NHS.

Published economic analysis exists for Australia and New Zealand, not the UK; neither showed a clear cost-effectiveness advantage. CCR-modelled drug acquisition for a full seven-day course is about £24,052 per 1,000 at the January 2026 tariff price. Patient-level administration, monitoring, actual duration, vasopressor offset and transfusion-resource effects are required for a full model. Not defensibly estimated from the trial alone; use current ICNARC septic-shock volume, persistent-vasopressor eligibility and existing steroid uptake.

• Current listed drug price — Observed: The January 2026 NHS Drug Tariff listed hydrocortisone 100 mg powder for injection at £17.18 per 10-vial pack. This is a tariff/list price, not a guaranteed local procurement price.
• Maximum seven-day regimen — CCR-modelled: Hydrocortisone 200 mg/day for seven days requires 14 x 100 mg vials: approximately £24.05 per patient or £24,052 per 1,000, excluding pharmacy preparation, IV administration, glucose/electrolyte monitoring and adverse-event management.
• Non-UK cost-effectiveness — Published economic analysis: Australian analysis: incremental hospital cost A$3,767 per patient (95% CI -A$2,891 to +A$10,425), approximately 0.10 QALYs in both groups and ICER A$1.254 million/QALY. New Zealand analysis found no value advantage and about 55% probability of cost-effectiveness. Neither is directly transferable to NHS prices.

Public investment

Not publicly verified — National Health and Medical Research Council of Australia; Health Research Council of New Zealand; indirect UK NIHR support; award NHMRC 1004108 and 1124926; HRC NZ 12/306.

Funding scope

Published grant references verified; amount not publicly verified and UK support was indirect. The primary publication verifies the funders and award references, but no consolidated trial award value or discrete UK contribution was identified. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The multinational funding produced a 3,800-patient trial that excluded a 90-day mortality benefit from hydrocortisone while showing faster shock reversal, shorter initial ventilation and less transfusion. A subsequent economic analysis extended the output, but a single cash return cannot be calculated because the total and UK-specific awards were not reported together.

ADRENAL supplied precise estimates for a cheap, familiar generic treatment and separated faster physiological recovery from survival and bed-day outcomes. UK participation leveraged a large international network; any capacity claim should remain cautious because ICU and hospital length of stay did not improve.

Define the persistent vasopressor requirement that triggers treatment and a clear stop rule. Standardise steroid-equivalent dosing and monitor glucose, sodium, potassium, infection, weakness and delirium. Audit shock duration, steroid exposure and transfusion; do not book ICU or hospital bed savings without local patient-level evidence.

Observed: mortality confidence interval includes clinically important benefit and harm. Earlier shock resolution did not translate into demonstrated ICU or hospital length-of-stay reduction. Economic evidence used non-UK prices and systems; NHS value remains uncertain despite low generic drug cost.

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• Surviving Sepsis Campaign guideline ↗ (opens in a new tab)
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• PubMed record ↗ (opens in a new tab)

Observed: neutral time to liberation; approximately 99 fewer patients received antibiotics for respiratory infection per 1,000, but about 143 more were reintubated. Median invasive ventilation was three days shorter, which must not be converted into aggregate bed-days.

Neutral primary outcome with mixed secondary effects; economic conclusion is too uncertain for universal implementation.

Published economic analysis: six-month point estimate £302 lower cost and 0.02 more QALYs per patient, but confidence intervals were wide and probability of cost-effectiveness only 57% to 59%. Five-year value was driven by uncertain survival extrapolation.

Published economic analysis: six-month point estimate £302 saving per patient with wide uncertainty; five-year conclusion was highly assumption-sensitive. Calculated from the six-month analysis: point estimate £302,000 saving per 1,000; 95% interval spans £5.490 million saving to £4.760 million additional cost. This must not be booked as cash-releasing savings. Not estimated.

• Standalone NIV pathway price — Not available: No single transferable device price was reported. Local costing must include machine availability, interface, circuit/filter, humidification, nurse/physiotherapist training, monitoring and emergency reintubation capacity.
• Six-month NHS/PSS analysis — Published economic analysis: In 2016 GBP, incremental cost was -£302 per patient (95% CI -£5,490 to +£4,760), incremental QALY +0.02 (95% CI -0.01 to +0.05), with only 57% to 59% probability of cost-effectiveness.
• Five-year extrapolation and workforce dependence — Published economic analysis: Base-case five-year cost was £1,972 higher with 0.427 more QALYs, ICER £4,618/QALY. Under equal-survival assumptions it was £6,453 more costly and 0.092 QALYs worse. COPD probability of cost-effectiveness was 82% to 87%; safe delivery requires experienced NIV and immediate airway staff.

Public investment

£1,192,962.91 — NIHR Health Technology Assessment programme; award 10/134/06.

Funding scope

Verified NIHR award value. Nominal awarded amount in the NIHR Funding and Awards record; no inflation adjustment. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.193 million award delivered a 364-patient randomised trial in 41 NHS ICUs, health-economic work and a full HTA report. It showed that a protocol of early extubation to non-invasive ventilation did not shorten liberation from all ventilation, despite less invasive ventilation and respiratory antibiotic use, and it identified a higher reintubation rate.

The result prevents universal rollout of a complex pathway requiring non-invasive-ventilation capacity, trained staff and close reintubation surveillance. It also preserves a more focused research and clinical role for non-invasive weaning in selected patients rather than treating the neutral primary outcome as evidence that the component technology has no value.

Use explicit selection criteria, including ability to protect the airway and tolerate NIV, and avoid extrapolation to all difficult-to-wean patients. Maintain 24/7 capability for close monitoring and prompt reintubation; increased reintubation is a core safety and workforce consequence. Audit reintubation, invasive-ventilation exposure, total ventilation, respiratory infection, ICU stay and subgroup outcomes, especially COPD.

Open-label trial with a neutral primary outcome and mixed secondary outcomes. Only approximately half the sample had a complete QALY profile before imputation. Long-term cost-effectiveness was driven by survival extrapolation and changed direction under plausible alternative assumptions.

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Observed: 6 fewer favourable neurological survivors per 1,000 with i-gel, compatible with 16 fewer to 4 more; initial ventilation success improved by 83 per 1,000. Regurgitation and aspiration differences were uncertain.

Neutral patient-centred primary outcome; better procedural success did not translate into neurological benefit.

Published economic analysis: the advanced-airway equipment used cost about £7 versus £13 per case, but total six-month cost was £157 higher with i-gel and QALYs were 0.0015 lower; neither strategy had an economic advantage.

Published economic analysis: roughly £6 lower airway-equipment cost but £157 higher total six-month cost per i-gel patient, with wide uncertainty and no QALY gain. NIHR award 12/167/102 is verified; award amount is not stated here. Calculated: about £6,000 lower advanced-airway equipment cost but £157,000 higher total six-month cost per 1,000 i-gel-strategy patients (95% CI £270,000 lower to £583,000 higher). Do not treat either point estimate as cash-releasing. Not estimated: current ambulance-service airway strategy, arrest volume and provider-level eligibility must be used locally.

• Airway consumables in 2017/18 GBP — Published economic analysis: i-gel £4.88; tracheal tube £0.78, laryngoscope handle £2.71, blade £2.78 and bougie £10.86. Actual mean advanced-airway equipment cost was approximately £7 with i-gel versus £13 with intubation, £6 lower per patient.
• Six-month total cost — Published economic analysis: Mean NHS/PSS cost was £3,570 with i-gel versus £3,413 with tracheal intubation; incremental £157 per patient (95% CI -£270 to +£583).
• Health outcome, training and capacity — Published economic analysis: Incremental QALY was -0.0015 (95% CI -0.0059 to +0.0028); neither strategy had a cost-effectiveness advantage. Service choice must include ongoing paramedic training, skill retention, device stock, quality assurance and rescue-airway capacity.

Public investment

£1,947,278.86 — NIHR Health Technology Assessment programme; award 12/167/102.

Funding scope

Verified NIHR award value. Nominal awarded amount in the NIHR Funding and Awards record; no inflation adjustment. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.947 million award randomised 1,523 paramedics from four English ambulance services and enrolled 9,296 patients, with economic and six-month outcome analyses. It found no improvement in favourable neurological outcome with an i-gel-first strategy, while showing better initial ventilation success and allowing procurement and training decisions to be based on comparative evidence.

The neutral primary outcome permits services to retain both advanced-airway strategies and concentrate on competency, rescue techniques and local system reliability rather than claiming that one device is clinically superior. The cluster design also demonstrated a scalable method for trials embedded in ambulance practice.

Allow service-level selection of either initial strategy while maintaining a clear failed-airway and oxygenation rescue algorithm. Protect competence through ongoing training, supervised practice and audit of attempt number, ventilation success, aspiration and neurological outcome. Do not use initial ventilation success alone as the service endpoint; patient-centred outcomes were neutral.

Cluster allocation by paramedic produced crossover and missing airway attempts, reflecting real practice but diluting strategy separation. Favourable neurological outcome was uncommon and the confidence interval includes small benefit and harm. Equipment prices were 2017/18 values; workforce and training costs may dominate the £6 consumable difference.

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Observed: PTSD symptom difference -0.03 points (95% CI -2.58 to +2.52) against a prespecified clinically important difference of 4.2 points; likely PTSD and other psychological/quality-of-life outcomes were not improved.

Neutral primary and secondary outcomes; discontinue the tested universal package while protecting risk-based psychological support.

Published economic analysis: intervention delivery cost £140 per patient or £140,000 per 1,000. Total cost and QALY differences were highly uncertain; probability of cost-effectiveness was about 60%, insufficient to rescue a clinically neutral intervention.

Published economic analysis: £140 intervention cost per patient with highly uncertain total-cost and QALY results. NIHR HS&DR award 12/64/124 is verified; award amount is not stated here. Calculated: £140,000 direct programme-delivery cost per 1,000 patients at the historical estimate. The total-cost point estimate suggests £755,000 lower cost but ranges from £5.883 million lower to £4.374 million higher and is not a cash-saving case. Not estimated: determine current use of the exact POPPI package and eligible ventilated ICU population locally; do not count savings from services that were never commissioned.

• Intervention delivery — Published economic analysis: Historical intervention cost was £140 per patient: £6 assessment, £109 stress-support sessions, £4 training and £21 debriefing; £140,000 per 1,000 before price-year update.
• Six-month cost and QALY — Published economic analysis: Incremental total cost was -£755 per patient (95% CI -£5,883 to +£4,374) and incremental QALY +0.004 (95% CI -0.023 to +0.031).
• Net benefit and workforce release — Published economic analysis: Incremental net monetary benefit was £835 (95% CI -£4,322 to +£5,992), with about 60% probability of cost-effectiveness. Stopping the tested package can release assessment/session/training/debriefing nurse time, but should not remove targeted psychology capacity.

Public investment

£2,005,375.09 — NIHR Health and Social Care Delivery Research programme; award 12/64/124.

Funding scope

Verified NIHR award value. Nominal awarded amount in the NIHR Funding and Awards record; no inflation adjustment. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £2.005 million award funded intervention development, two feasibility phases, a 1,458-participant cluster trial across 24 UK ICUs and a lifetime economic evaluation. The package did not reduce post-traumatic stress symptom severity, providing actionable evidence not to commission a universal labour-intensive programme in this form.

The negative result protects nurse time otherwise required for training, repeated stress assessments and support sessions, while leaving compassionate communication, targeted screening and clinically indicated psychology referral intact. The project also generated transferable methods for developing and testing complex critical care interventions.

Do not commission the exact universal POPPI package as a PTSD-prevention intervention. Preserve risk-based screening, trauma-informed care, communication and referral to qualified psychological services. If deimplementing an existing package, measure nurse time released and monitor PTSD, anxiety, depression and access to follow-up care.

Observed: approximately 21.2% primary-outcome data were missing, increasing uncertainty despite adjusted analysis. Complex intervention fidelity and cluster-level implementation varied. Economic confidence intervals were very wide and the intervention had no clinical-effectiveness signal.

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Observed: 29 fewer 90-day deaths per 1,000, compatible with 68 fewer to 11 more. Vasopressor duration was 9.9 hours shorter on average and dose 12.8 mg lower, without demonstrated organ-support, bed-day or cognitive benefit.

Supports selective safe de-intensification and reduced drug exposure; survival and economic advantages remain uncertain.

Published economic analysis: vasopressor drug cost was £21 lower per patient. Adjusted total 90-day cost was £311 lower and incremental net monetary benefit £378, but both had wide intervals; probability of cost-effectiveness fell from 70% at 90 days to 40% at one year.

Calculated: £21,000 lower vasopressor acquisition and £311,000 lower adjusted 90-day total cost per 1,000 on point estimates; the total-cost 95% interval spans £2.042 million saving to £1.420 million additional cost. Not estimated: use current ICNARC data for patients aged 65 or older receiving vasopressors for vasodilatory hypotension and current MAP-target practice.

• Vasopressor drug use — Observed: Within-trial vasopressor acquisition cost was £83 versus £104, £21 lower per patient or £21,000 per 1,000 in the trial price year.
• Ninety-day NHS/PSS cost and QALY — Published economic analysis: Adjusted total cost difference -£311 per patient (95% CI -£2,042 to +£1,420); incremental QALY +0.003 (95% CI -0.0004 to +0.007).
• Net benefit and implementation resource — Published economic analysis: Incremental net monetary benefit at £20,000/QALY was £378 (95% CI -£1,347 to +£2,103); probability of cost-effectiveness 70% at 90 days and 40% at one year. No capital equipment is needed, but protocols, prescribing targets, education and perfusion/safety monitoring are required.

Public investment

£1,242,497.00 — NIHR Health Technology Assessment programme; award 15/80/39.

Funding scope

Verified NIHR award value. Nominal awarded amount in the NIHR Funding and Awards record; no inflation adjustment. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.242 million award delivered a pragmatic 2,600-patient trial in 65 UK ICUs with economic and cognitive follow-up. It showed that a mean arterial pressure target of 60–65 mm Hg in selected older patients reduced vasopressor exposure without a statistically significant difference in the unadjusted 90-day mortality outcome.

The strategy needs no new device and can reduce drug exposure, acquisition and preparation, but it requires clear exceptions and perfusion monitoring. The trial also demonstrated the value of linking a national critical care trials unit and audit infrastructure; no ICU or hospital bed-day saving was demonstrated.

Create an age- and phenotype-specific MAP target with clear exceptions for individual perfusion concerns. Update bedside and electronic prescribing guidance, educate staff and monitor for protocol separation without delayed rescue. Audit mortality, vasopressor exposure, acute kidney support, arrhythmia/ischaemia, cognition and length of stay.

The unadjusted primary mortality result was not statistically significant; the favourable adjusted odds ratio should not be over-interpreted. The trial was open label and actual target separation was modest. Economic benefit was imprecise and sensitive to follow-up horizon, falling to 40% probability of cost-effectiveness at one year.

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Calculated: mortality was essentially identical, about 2 more deaths per 1,000 with acceleration, compatible with roughly 34 fewer to 38 more. Accelerated initiation caused about 350 extra renal-replacement starts, 44 extra dialysis-dependent survivors and 66 extra patients with adverse events per 1,000.

Definitive neutral mortality trial with strong treatment-avoidance and harm signals supporting standard initiation.

No UK economic evaluation was available, but standard timing directly avoids temporary dialysis catheters, machines, circuits, fluids, anticoagulation, laboratory and specialist/nursing workload in about 350 patients per 1,000. These resources should be valued with local PLICS data rather than generic bed-day assumptions.

Not available for the UK. A later Canadian model is informative but not transferable. NIHR HTA award 17/42/74 is verified; amount is not stated here. CCR-modelled: value 350 avoided starts per 1,000 with local modality, treatment-count, catheter, consumable and workforce data; add avoided chronic dialysis associated with 44 fewer dependent survivors per 1,000 survivors. No aggregate dialysis-day or ICU-day claim is made. Not estimated: use ICNARC severe-AKI volume after excluding urgent indications and current accelerated-initiation share.

• UK economic evaluation — Not available: No trial-based NHS cost-effectiveness analysis or transferable UK per-session cost was reported.
• Avoidable treatment components — Observed: A standard strategy avoided renal-replacement initiation in about 350 patients per 1,000, reducing temporary catheter insertion, machine time, circuits, replacement/dialysate fluid, anticoagulation, laboratory testing and critical care renal/nursing workload.
• Local capacity and downstream model — CCR-modelled: Use local PLICS for catheter, modality-specific sessions, consumables and staff minutes, plus chronic dialysis following the observed 44 extra dependent survivors per 1,000 survivors. A 2025 Alberta model in Canadian dollars favoured standard initiation but is not transferable to the NHS.

Public investment

£699,561.00 — NIHR Health Technology Assessment programme; award 17/42/74.

Funding scope

Verified UK-arm award value. Nominal NIHR award for the UK arm, not the total international trial budget; no inflation adjustment. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £699,561 UK-arm award contributed to a 3,019-patient trial at 168 hospitals in 15 countries. The international collaboration showed no mortality advantage from accelerated renal-replacement therapy and found that a standard strategy avoided treatment in about 350 patients per 1,000 while reducing dialysis dependence and adverse events.

This is a high-leverage UK contribution to global evidence with direct capacity implications: standard initiation can avoid temporary dialysis catheters, machines, circuits, replacement or dialysate fluid, anticoagulation, laboratory testing and specialist nursing workload. Reduced disposable and fluid use is environmentally relevant, but the trial did not measure carbon emissions or UK cash-releasing savings.

Remove time-triggered accelerated initiation when there is no urgent metabolic, fluid or toxin indication. Implement frequent biochemical, urine-output, respiratory and clinical monitoring with explicit rescue triggers and rapid access to renal-replacement therapy. Audit starts avoided, emergency rescue, catheter complications, adverse events, 90-day mortality and dialysis dependence.

Open-label strategy trial; exact standard-care triggers and baseline practice vary across units. Results do not support delaying therapy when an urgent indication is present. NHS cash savings depend on whether released machine, consumable and staff capacity can be redeployed; no UK economic analysis quantified this.

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• PubMed record ↗ (opens in a new tab)
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Observed Bayesian primary outcome: fixed hydrocortisone had a 93% probability and shock-dependent hydrocortisone an 80% probability of superiority for organ-support-free days, below the prespecified 99% threshold. Calculated fixed-course mortality was about 34 fewer per 1,000, compatible with roughly 154 fewer to 86 more.

Platform domain stopped early and underpowered; it supports the corticosteroid class in context, not regimen superiority or quantified bed-day savings.

Not available: no trial-based UK cost-effectiveness analysis or reliable regimen price was reported. Hydrocortisone is generic, but repeated IV dosing uses pharmacy, line and nursing capacity and requires glucose, infection, delirium and neuromuscular monitoring.

Not available: no trial-based UK economic evaluation or regimen-level acquisition cost. Not available: locally price the chosen steroid-equivalent regimen and repeated administration. No aggregate organ-support-day or bed-day saving should be monetised from the reported median/ordinal outcome. Not estimated: the severe-COVID eligible population and current steroid choice vary materially over pandemic waves and calendar time.

• Treatment regimen — Observed: Fixed treatment used hydrocortisone 50 mg or 100 mg IV every six hours for seven days, up to 28 administrations; shock-dependent treatment continued while shock was present.
• UK price and economic evaluation — Not available: The domain reported neither a reliable UK acquisition price for its mixed dosing regimens nor an NHS cost-effectiveness analysis.
• Delivery and capacity consequence — Not available: Costing should include generic drug, pharmacy preparation, repeated IV administration, line access and glucose/infection/delirium/neuromuscular monitoring. No credible ICU or hospital bed-day saving can be derived from the medians.

Public investment

£1,200,000 — UK government and NIHR support for the REMAP-CAP platform, alongside multiple international funders; funding reference/scope Platform-wide support; the corticosteroid domain had no additional domain-specific funding.

Funding scope

Verified UK platform-wide support; not a hydrocortisone-domain grant value. UK government statement published in January 2021. This is support for the whole REMAP-CAP platform and must not be attributed to the hydrocortisone domain alone. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.2 million UK support applied across REMAP-CAP rather than this comparison alone. Within the corticosteroid domain, the established platform randomised 614 critically ill patients rapidly and delivered a prespecified estimate during the pandemic; the domain stopped early after external steroid evidence and did not meet its own superiority threshold, so a stand-alone financial return would be misleading.

The principal return was reusable pandemic research infrastructure: the same sites, governance, data systems and adaptive methods generated answers across several treatment domains. UK hospitals supplied a large share of platform recruitment, and the hydrocortisone analysis contributed to the wider corticosteroid evidence base; attribution should remain platform-wide and no environmental outcome was measured.

Use one steroid-equivalent protocol and prevent duplicate hydrocortisone plus dexamethasone prescribing. Specify start/stop criteria and route, with monitoring for hyperglycaemia, secondary infection, delirium, sodium/fluid effects and weakness. Treat hydrocortisone as an alternative within a class recommendation, not as a proven superior regimen; audit steroid exposure and organ support.

The domain stopped early after external corticosteroid results and included only 101 concurrent controls, leaving wide credible intervals. Approximately 15% of patients assigned no hydrocortisone received systemic corticosteroids, reducing treatment separation. Pandemic-era practice, variants, vaccination and background therapy limit current transportability; no regimen-specific economic analysis exists.

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• Corticosteroid domain funding appendix ↗ (opens in a new tab)

28 fewer 28-day deaths per 1,000 overall and 121 fewer per 1,000 among patients already ventilated; no indication without respiratory support.

Large UK platform RCT with high confidence for the 2020 population; present-day absolute benefit is uncertain as variants, immunity and background care have changed.

A maximum oral course costs about £2; the published model estimated £31.66 incremental cost, 0.025 QALY gained and an ICER of £1,247/QALY per patient.

Published model: £31.66 incremental cost, 0.025 QALY and £476 net monetary benefit per patient at £20,000/QALY. Calculated: about £2,010 for 1,000 maximum oral courses; the economic model scales to £31,660 incremental cost, 25 QALYs and £476,000 net monetary benefit per 1,000. Cash or bed-capacity savings are not available from mean patient-level bed-days. Not available for current forecasting. A published historical NHS model estimated about 22,000 UK lives saved from July 2020 to March 2021; this was modelled rather than trial-observed. A historical scenario may apply 0.121 to ventilated and 0.029 to oxygen-only eligible patients, with intervals and current-era caveats.

• Drug acquisition — Calculated: A maximum oral course uses 30 × 2-mg tablets and costs about £2.01 using the current tariff proxy of £3.35 per 50-tablet pack. The published economic input was £0.23/day or £2.30/course in 2020 prices. IV preparation is needed only when enteral dosing is unsuitable.
• Cost-effectiveness — Published economic analysis: Incremental cost £31.66 and gain 0.025 QALY per patient; ICER £1,247/QALY and incremental net monetary benefit £476/patient at £20,000/QALY. This is health value, not a cash-releasing saving.
• Workforce and capacity — Observed: No capital equipment and minimal oral administration burden. Hospital stay medians were 12 versus 13 days, but patient-level mean bed-days were not reported, so the median must not be multiplied into a capacity saving.

Public investment

£2.1 million initial award plus £19 million additional funding — UK Research and Innovation (UKRI) and National Institute for Health Research (NIHR), with later Wellcome and other shared platform support; award MC_PC_19056; Wellcome 222406/Z/20/Z.

Funding scope

Verified shared platform funding; no dexamethasone-comparison or marginal arm budget has been published. Nominal public awards made in 2020 for the whole RECOVERY platform The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The comparison randomised 6,425 patients and established a very low-cost treatment with a mortality benefit in patients requiring oxygen or ventilation. Historical UKRI modelling attributed about 22,000 UK and one million global lives saved to uptake by early 2021, but those are modelled estimates; the £21.1 million was platform-wide and must not be presented as a dexamethasone-specific return.

Rapid incorporation into national and international guidance demonstrated the value of a simple, embedded platform during an emergency. Dexamethasone is generic, orally available, heat-stable and requires no capital equipment, supporting equitable deployment and preserving a low-burden pandemic-treatment pathway; eligibility safeguards remain important because benefit was not shown without an oxygen requirement.

Use an automated eligibility prompt linked to oxygen or hypoxia, with a hard stop when no oxygen is required. Use oral dosing first, stop at discharge, and monitor glucose, infection, gastrointestinal bleeding and mental-state complications. Retain prescribing and stock pathways as pandemic-preparedness infrastructure.

Open-label trial and subgroup absolute-effect intervals. Current-era indirectness because baseline risk, immunity, variants and background treatments have changed. The economic model used 2020 prices and structural long-COVID assumptions; median stay is not mean bed-days.

• Primary paper ↗ (opens in a new tab)
• Accessible primary copy ↗ (opens in a new tab)
• Current NICE therapeutics ↗ (opens in a new tab)
• NHS tariff product ↗ (opens in a new tab)
• Economic analysis ↗ (opens in a new tab)
• Historical NHS lives estimate ↗ (opens in a new tab)
• Platform funding ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)

No survival or functional benefit; 74 more haemodynamically important arrhythmias per 1,000 with routine 33°C.

Large international RCT providing strong evidence against routine 33°C for the enrolled phenotype; selected subgroups remain uncertain.

Deimplementation can avoid some cooling consumables, device time, sedation and neuromuscular blockade, but about 46% still required device cooling for fever.

Not available as a trial economic evaluation. The available device prices are historical NICE list or proxy values from 2017. CCR-modelled illustration: about £376,000–£450,000 avoided historical all-in Arctic Sun expenditure if 540 device treatments are avoided, plus a point estimate of 74 haemodynamically important arrhythmias avoided. Do not assume all cooling-device use disappears. Not available. A reliable denominator for comatose TTM2-eligible UK OHCA survivors, current device uptake and procurement prices is required. No UK-attributable trial grant was identified.

• Within-trial economics — Not available: No economic evaluation was reported. Both strategies require core-temperature monitoring and active fever treatment; routine 33°C adds cooling and rewarming protocols, device time, shivering assessment, sedation or analgesia and often neuromuscular blockade.
• Historical device-price proxy — Published economic analysis: NICE MIB112 (2017) estimated Arctic Sun at £697–£833 per treatment, including £556–£738 single-use items; Blanketrol single-use items £129–£347; and Thermogard capital £21,500 plus catheter £318–£638. These are historical proxies, not current NHS procurement prices.
• Potential deimplementation — CCR-modelled: If device cooling fell from 100% to the 46% observed in the normothermia arm, 540 of 1,000 device treatments would be avoided. At historical Arctic Sun all-in estimates this is about £376,000–£450,000 per 1,000; consumables are the immediate cash-releasing element and capital savings arise mainly at replacement.

Public investment

A$4,021,238 total of the four funding amounts listed by ANZICS — Swedish Research Council, Swedish Heart-Lung Foundation, Stig and Ragna Gorthon Foundation, and Knutsson Foundation, with additional unpriced regional and foundation support; award Swedish Research Council 2016-00428.

Funding scope

Verified listed funding, but not a complete trial-cost account; further support was acknowledged without amounts. AUD equivalents displayed by ANZICS; conversion date and basis are not stated The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

In 1,900 participants, TTM2 showed no survival or functional advantage from routine cooling to 33°C over protocolised normothermia with fever treatment, while haemodynamically important arrhythmias increased. This provides high-value deimplementation evidence, although no formal economic evaluation was done and about 46% of the normothermia group still required a cooling device.

Services can move from obligatory 33°C cooling towards continuous temperature monitoring and active fever prevention, potentially reducing cooling consumables, sedation, neuromuscular blockade and protocol workload. The trial does not justify abandoning temperature control, and benefits for poorly represented subgroups remain uncertain.

Rewrite postarrest protocols around fever prevention at no more than 37.5–37.7°C for at least 72 hours, while preserving continuous core-temperature monitoring. Define rescue-device criteria and audit fever exposure, device use, arrhythmia, sedation and neuromuscular blockade. Train teams that protocolised normothermia does not mean permissive fever.

Open-label intervention and no formal NHS cost study; current device prices are local and often confidential. About 46% of normothermia patients still received device cooling. Potential benefit from 32–34°C in under-represented subgroups remains uncertain.

• Primary paper ↗ (opens in a new tab)
• PubMed results ↗ (opens in a new tab)
• Supplement with length of stay ↗ (opens in a new tab)
• ERC–ESICM temperature guideline ↗ (opens in a new tab)
• ILCOR recommendation ↗ (opens in a new tab)
• NICE historical device costs ↗ (opens in a new tab)
• Sedation and NMBA post-hoc analysis ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)

No mortality benefit; 221 more serious adverse events and 45 more intracranial haemorrhages per 1,000, with 2.1 fewer mean ventilator-free days per patient.

UK multicentre RCT stopped early after 412 of 1,120 planned participants; mortality is imprecise, but clinical safety and economic directions were consistently unfavourable.

ECCO₂R required £3,650 direct disposables and cost £7,668.76 more per patient at 12 months in 2018/19 prices; standard care dominated.

Published 2018/19 analysis found £7,668.76 higher 12-month cost per patient and no QALY gain; standard ventilation dominated. Trial devices and consumables were supplied without charge, so trial procurement expenditure does not represent NHS deployment cost. Calculated from the published analysis: avoiding ECCO₂R avoids £3.65m direct disposables and has a central 12-month health-service saving of £7.67m per 1,000, with trial CI about £0.16m–£15.18m before inflation. It may also avoid about 221 serious adverse events and 45 intracranial haemorrhages. Cash release depends on contracts and sunk capital. Not available: only 6% of screened patients entered the trial. Use reproducible trial eligibility, ICNARC case-mix data, current uptake and procurement records rather than national ARDS counts. NIHR HTA award 13/143/02 funded the study, but a reliable award amount was not retrieved.

• Direct consumables — Published economic analysis: At 2018/19 prices, the cartridge cost £3,000 and catheter £650: £3,650 direct disposable cost per treated patient. Capital and support costs were not included.
• Twelve-month cost and QALY — Published economic analysis: ECCO₂R cost £7,668.76 more per patient (95% CI £159.75 to £15,177.77), with QALY difference -0.01 (95% CI -0.06 to +0.05). Imputed base case was +£7,900 and -0.008 QALY; standard ventilation dominated and cost-effectiveness probability was 0% at £0–£50,000/QALY.
• Equipment and workforce — Observed: Requires an ECCO₂R console, cartridge and circuit, large-bore vascular catheter, systemic anticoagulation, insertion skills, priming and continuous specialist nursing and medical oversight, with bleeding, thrombosis, access and device-failure workload.

Public investment

£1,668,029.80 — National Institute for Health Research Health Technology Assessment programme; award 13/143/02.

Funding scope

Verified trial-specific public award. Current award total displayed in the NIHR Funding and Awards database; nominal award basis The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

REST recruited 412 participants before early stopping and showed no mortality benefit, fewer ventilator-free days and substantially more serious adverse events with extracorporeal carbon dioxide removal. Its embedded analysis found £7,668.76 higher 12-month cost per patient in 2018/19 prices; avoiding 1,000 otherwise-planned uses would therefore avoid about £7.67 million on the central estimate, but that is an arithmetic scenario rather than a realised grant ROI.

The trial provides unusually strong evidence for device deimplementation and procurement governance: it identifies avoidable cartridge, catheter, anticoagulation, cannulation and specialist-monitoring burden as well as bleeding risk. It also shows why high-risk critical care devices need adequately powered comparative trials before routine adoption.

Remove the routine indication from local protocols and restrict ECCO₂R to research ethics-approved trials. Stop disposable procurement or minimum-volume commitments where possible and account separately for sunk capital. Retrain cannulation and anticoagulation teams as needed, retain research governance, and audit residual off-trial use and complications.

Trial stopped early and recruited only 412 of 1,120 planned participants; only 6% of screened patients enrolled. Many centres were initially device-naïve; current devices and tender prices may differ. Economic data are in 2018/19 prices and used imputation, but these limitations do not provide evidence of clinical benefit.

• Primary paper ↗ (opens in a new tab)
• Full text ↗ (opens in a new tab)
• Economic analysis ↗ (opens in a new tab)
• Economic full text and price year ↗ (opens in a new tab)
• Resource-use appendix ↗ (opens in a new tab)
• NIHR synopsis ↗ (opens in a new tab)
• Funding ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)

Adjusted point estimate of 41 fewer survivors and observed 14 more major bleeds per 1,000 with therapeutic dosing; no organ-support benefit.

Large international multiplatform adaptive RCT stopped for futility, with 99.9% posterior probability of futility and 95.0% probability of inferiority for the primary outcome.

Deimplementation avoids higher-dose drug, additional injections or infusion, monitoring and bleeding-management workload; no trial economic analysis quantified cash savings.

Not available as a formal economic evaluation. The trial established futility and likely inferiority of therapeutic dosing in critically ill COVID-19 rather than a cash-saving estimate. Avoidance removes incremental heparin, injection or infusion, laboratory and dose-adjustment costs and may avoid 14 major bleeds per 1,000 on the point estimate. Drug savings depend on weight, renal function, duration, agent and hospital tender price; the tariff examples add about £8.00–£14.56 per day in 70–100 kg illustrations. Not available because current critical care COVID-19 volume and baseline therapeutic-dose uptake differ substantially from 2020–21. Platform funding is spread across three international trials and cannot be attributed cleanly to this comparison.

• Illustrative LMWH drug cost — Calculated: Using the NHS Drug Tariff December 2024 rather than hospital tender prices, enoxaparin 40 mg ×10 cost £30.27, 80 mg ×10 £55.13 and 100 mg ×10 £87.93. For a 70-kg illustration, 80 mg twice daily versus 40 mg once daily adds about £8.00/day drug-only; for 100 kg it adds about £14.56/day.
• Administration and monitoring — Observed: Therapeutic LMWH uses higher and often twice-daily weight-based dosing. UFH needs an infusion pump, repeated APTT or anti-Xa sampling and adjustment. Both add pharmacy and nursing work, renal and weight adjustment, platelet surveillance and bleeding-management exposure.
• Bed-day and cash effect — Not available: No trial economic analysis quantified savings and there was no demonstrated survival or organ-support benefit. Do not monetise the three-day composite median as raw ICU bed-days.

Public investment

£1,237,495 for UK REMAP-CAP pandemic expansion; other platform awards and total comparison cost not aggregated — REMAP-CAP, ACTIV-4a and ATTACC platform funders, including UK NIHR/DHSC, EU PREPARE/RECOVER, US NHLBI/NIH, Canadian and Australasian agencies; award UK REMAP-CAP reference not publicly stated; PREPARE 602525; RECOVER 101003589; ACTIV-4a OTA-20-011 and 1OT2HL156812-01; multiple ATTACC awards.

Funding scope

Verified partial/shared funding only; no defensible marginal comparison budget or full multiplatform total is publicly available. Nominal shared platform awards; the trial was a harmonised three-platform comparison The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The multiplatform trial provided primary-outcome data for 1,098 critically ill patients and stopped for futility, showing that routine therapeutic-dose heparin did not improve survival or organ-support-free days in this group. That result prevents low-value escalation and its bleeding and monitoring burden, but it cannot be assigned a monetary ROI from any one platform's grant.

The work enabled severity-specific anticoagulation guidance and reduced injections, dose checks, laboratory review and bleeding exposure from inappropriate full-dose treatment. It also proved that independent adaptive platforms could prospectively harmonise methods and data during a pandemic; the critical care result must remain distinct from the separate benefit observed in non-critically ill patients.

Separate non-critical ward and organ-supported cohorts clearly in prescribing guidance and electronic orders. Default organ-supported patients to standard thromboprophylaxis and require a documented independent indication for therapeutic dosing. Perform medication review at ICU escalation, use renal and weight protocols, and audit bleeding and residual off-indication treatment.

Open-label; usual-care prophylaxis varied and sometimes included intermediate dosing. Early-pandemic population and exclusion of patients at high bleeding risk. Independent indications for therapeutic anticoagulation are unaffected, and the result differs from evidence in non-critically ill patients.

• Primary paper ↗ (opens in a new tab)
• Full text ↗ (opens in a new tab)
• PMC copy ↗ (opens in a new tab)
• NICE COVID anticoagulation recommendation ↗ (opens in a new tab)
• NHS Drug Tariff December 2024 ↗ (opens in a new tab)
• eMIT source and limitations ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)

CPAP: 80 fewer intubations or deaths per 1,000 (95% CI 10 to 150 fewer), driven by fewer intubations; mortality effect uncertain.

Positive primary outcome for CPAP; HFNO comparison null and underpowered after early stopping.

Potentially fewer intubations and ICU admissions, but no demonstrated reduction in ICU or hospital length of stay and no trial-based UK cost-effectiveness estimate.

Not available: no trial-based economic evaluation located. Do not monetise 80 avoided intubations by multiplying by a typical ventilator-day cost; the trial did not demonstrate an aggregate ICU/hospital day saving. Build a local model from patient-level bed-days, equipment availability, staffing and adverse events. Not defensibly estimated: current eligible COVID-19 admissions, CPAP uptake and service configuration vary materially over time.

• Device and consumable cost — Not available: The trial did not report a UK acquisition price or within-trial economic evaluation. Local costing must include CPAP generator/ventilator use, circuits, masks/helmets, filters, humidification, maintenance and oxygen consumption.
• Capacity — Observed: The trial shows fewer intubations and ICU admissions, but not shorter ICU/hospital stay. Among those intubated, median invasive ventilation was 15 versus 11 days; the between-group time-to-liberation analysis was not significant. This must not be multiplied to claim bed-days saved.
• Workforce and infrastructure — Not available: A safe CPAP pathway needs trained ward/critical care staff, frequent observations, fit/leak/pressure-injury management, escalation protocols, adequate oxygen supply and infection-control capacity. These were not costed in the trial.

Public investment

Not publicly verified — National Institute for Health Research; award COVID-19-RSC.

Funding scope

Funding source and reference verified; amount not publicly verified. NIHR award and reference reported by the investigators; no reliable public award total located The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The trial randomised 1,273 patients in 48 UK and Jersey hospitals and showed that an initial CPAP strategy reduced the composite of intubation or death, whereas high-flow nasal oxygen did not. The award amount and a trial-based economic evaluation are unavailable, so neither cost per outcome nor grant return can be calculated.

RECOVERY-RS directly informed surge respiratory-support pathways and the skills, monitoring and escalation needed to deliver CPAP outside conventional ICU settings. It offers a basis for avoiding some intubations but did not demonstrate shorter ICU or hospital stay; equipment, oxygen demand, infection control and workforce capacity therefore require local costing.

Maintain explicit CPAP eligibility, contraindication and intubation-escalation criteria. Audit pressure injury, pneumothorax/pneumomediastinum, vomiting/aspiration and delayed escalation. Treat HFNO as a separate choice; RECOVERY-RS did not demonstrate superiority over conventional oxygen.

Open-label trial, substantial crossover and clinician-determined intubation threshold. Recruitment stopped before the planned sample size because COVID-19 admissions fell and funding ended. Results are specific to COVID-19 acute hypoxaemic respiratory failure and pandemic-era UK pathways.

• Primary paper ↗ (opens in a new tab)
• Open full text ↗ (opens in a new tab)

Non-inferior liberation; 93 fewer children sedated and 45 fewer nasal injuries per 1,000, with no demonstrated mortality or intubation difference.

Positive non-inferiority result; length-of-stay and cost findings are supportive secondary/economic outcomes.

Published six-month analysis: £5,702 lower mean cost per patient (95% CI £75 to £11,328 lower), driven mainly by hospital/critical care use; uncertainty remains around QALYs.

HFNC reduced adjusted six-month costs by £5,702 per patient (2019 GBP), with a CI just excluding zero; index hospital stay was the main cost driver. Published estimates scale to £5.702 million lower cost per 1,000 (95% CI £0.075 million to £11.328 million lower). The point estimate was 3 fewer QALYs per 1,000, compatible with 10 lost to 4 gained. Not defensibly estimated from the publication. Apply the per-patient cost distribution to PICANet-derived eligible volumes and the change in local HFNC/CPAP uptake.

• Six-month NHS/PSS cost — Published economic analysis: Mean cost £20,335 HFNC versus £24,142 CPAP; adjusted incremental cost -£5,702 per patient (95% CI -£11,328 to -£75), in 2019 GBP.
• Six-month QALY and net benefit — Published economic analysis: Incremental QALY -0.003 (95% CI -0.010 to +0.004); incremental net benefit at £20,000/QALY £5,628 (95% CI -£8 to +£11,264).
• Device/staff assumption — Published economic analysis: No additional intervention cost was included because devices and interfaces were already in use. HFNC is perceived as easier to use and less dependent on specialist nursing than CPAP, but capital, consumables, oxygen demand and maintenance were not separately priced.

Public investment

£1,382,564.50 for the complete FIRST-ABC programme — National Institute for Health Research Health Technology Assessment programme; award 17/94/28.

Funding scope

Verified master-protocol/programme award; it must not be counted in full against each trial. Current NIHR award total; shared by the Step-up and Step-down randomised trials The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

Step-up randomised about 600 children and showed high-flow nasal cannula was non-inferior to CPAP for liberation from respiratory support, with less sedation and nasal trauma. A later analysis estimated £5,702 lower six-month cost per patient in 2019 GBP, driven by hospital use, but this needs local validation and cannot be presented as the return on the whole shared FIRST-ABC award.

The result supports a more tolerable first-line option in acute paediatric illness while retaining CPAP rescue and escalation capability. Potential workforce and bed-use benefits are important but depend on local devices, oxygen supply and staffing; the finding must not be extrapolated to post-extubation care, where Step-down reached a different conclusion.

Ensure HFNC and CPAP rescue are both available; one in five HFNC patients switched to CPAP. Use standardised assessment, weaning and escalation criteria, and audit treatment failure. Keep the step-up and post-extubation indications separate in protocols and guidance.

Unblinded pragmatic non-inferiority trial with frequent crossovers and heterogeneous diagnoses. Reasons for shorter mean stay with HFNC were unclear and the secondary outcomes were not the primary non-inferiority target. Economic analysis used imputation and 2019 GBP and assumed no new device cost.

• Primary paper ↗ (opens in a new tab)
• Economic evaluation ↗ (opens in a new tab)
• NIHR HTA report ↗ (opens in a new tab)
• NIHR award 17/94/28 ↗ (opens in a new tab)

Primary outcome +2.9 days alive out of hospital (95% CI -1.2 to +7.0; not significant); secondary mortality signal 69 fewer deaths per 1,000 (95% CI 6 to 130 fewer).

Neutral primary outcome; mortality finding hypothesis-generating despite prespecification.

Drug acquisition is low, but a median course required 13 IV doses plus delirium assessment and safety monitoring; hospital stay was not shorter.

Not available. Routine scheduled use would imply roughly £57,000 to £88,000 acquisition cost plus 13,000 IV administrations per 1,000 treated at the median exposure. Deimplementation saves these only where such routine use currently occurs; the trial does not support withholding symptom-control treatment from selected agitated patients. Not defensibly estimated without the number of ICU delirium cases currently receiving scheduled IV haloperidol.

• Treatment exposure — Observed: Median 3.6 treatment days, 13 doses and 32.5 mg cumulative haloperidol; median daily dose 8.3 mg. Protocol dose was 2.5 mg IV three times daily plus as-needed doses, maximum 20 mg/day.
• 2026 UK drug acquisition illustration — CCR-modelled: NHS indicative prices found were £22.01 per five 5 mg/1 mL ampoules (£4.40 each) and £67.89 per ten (£6.79 each). If each 2.5 mg IV administration uses one single-use ampoule, a 13-dose median course is about £57 to £88 before hospital discounts, pharmacy and administration costs.
• Economic evaluation — Not available: No trial-based UK cost-effectiveness analysis was identified. Resource use includes twice-daily delirium screening, 13 IV administrations at the median, ECG/QTc and electrolyte review where indicated, adverse-effect surveillance and rescue-medication planning.

Public investment

DKK 7,025,000 minimum stated cash funding; additional institutional and foundation support not valued — Innovation Fund Denmark and Regional Medicines Foundation, with additional support from Zealand University Hospital and other foundations; award 4108-00011B; R124-2651.

Funding scope

Verified minimum trial funding; not a complete economic cost. Protocol-stated nominal awards: DKK 5,900,000 plus DKK 1,125,000 The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

AID-ICU randomised 1,000 patients and found no improvement in days alive and out of hospital with scheduled intravenous haloperidol. The result supports deimplementation of routine treatment and can avoid a median 13 intravenous administrations per treated patient plus monitoring workload; no trial-based economic evaluation converts this into a financial return.

The trial strengthens medication stewardship and can reduce nursing administration, pharmacy supply, QT/electrolyte review and adverse-effect surveillance for routine scheduled use. It does not support withholding targeted symptom-control treatment from selected distressed or dangerous patients, and the secondary mortality finding remains hypothesis-generating.

Retain multicomponent non-pharmacological delirium prevention and management as standard care. If haloperidol is used for dangerous distress/agitation, define indication, shortest duration, contraindications and daily stop review. Audit extrapyramidal reactions, QTc/arrhythmia, oversedation and rescue sedative use.

The trial was not positive for its primary endpoint; mortality was a component/secondary outcome and contrasted with MIND-USA. Open-label antipsychotic exposure after withdrawal occurred in part of the cohort, and detailed co-medication data were limited. The current UK ampoule prices are indicative community reimbursement prices, not confidential hospital procurement prices.

• Primary paper ↗ (opens in a new tab)
• One-year follow-up ↗ (opens in a new tab)
• 2026 indicative price: five ampoules ↗ (opens in a new tab)
• 2026 indicative price: ten ampoules ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)

No organ-support-free-day improvement; 8 additional major bleeds per 1,000 (95% credible interval 1 to 27 more).

Stopped for futility on the primary endpoint; secondary survival signal and definite bleeding harm.

Tablet cost is negligible; avoided bleeding, medication review and administration are the relevant savings. No economic evaluation.

Not available. Avoided 14-day generic acquisition is only about £470 to £640 per 1,000 for clopidogrel or aspirin at the cited tariff. The material resource consequence is avoiding an estimated 8 major bleeds per 1,000 if routine COVID-specific initiation would otherwise occur. Not estimated; routine COVID-specific use is not current standard care and severe-COVID volumes vary.

• Illustrative 2026 generic tablet cost — CCR-modelled: July 2026 Drug Tariff: aspirin 75 mg £1.28/28 tablets and clopidogrel 75 mg £0.94/28. A 14-day course is about £0.64 or £0.47 per patient respectively, before administration; other P2Y12 agents may cost more.
• Treatment duration and co-intervention — Observed: Antiplatelet treatment was continued in hospital for up to 14 days and was added to anticoagulant thromboprophylaxis, creating medication-review and bleeding-monitoring work.
• Economic evaluation — Not available: No trial-based UK economic evaluation was identified. Major-bleeding treatment, transfusion/endoscopy/procedures and additional stay are likely to dominate tablet cost.

Public investment

£1,237,495 for the UK pandemic expansion; wider international platform funding not aggregated — NIHR/DHSC UK REMAP-CAP pandemic expansion, alongside EU PREPARE/RECOVER, Australian NHMRC and other international platform funding; funding reference/scope UK award reference not publicly stated; PREPARE 602525; RECOVER 101003589; NHMRC APP1101719 and APP1116530.

Funding scope

Verified shared platform funding; no antiplatelet-domain or marginal comparison budget has been published. Nominal whole-platform UK pandemic-expansion funding reported to the UK COVID-19 Inquiry The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The domain randomised 1,557 critically ill patients and stopped for futility on organ-support-free days, while major bleeding increased. It prevented routine addition of a cheap but ineffective treatment whose downstream bleeding and monitoring costs would outweigh tablet acquisition; the shared platform award cannot be converted into a domain-level ROI.

The result supports medication stewardship, removal of COVID-only antiplatelet prompts and closer review of concomitant anticoagulation. Avoiding unnecessary treatment reduces administration and bleeding-related transfusion, procedures and bed use, while preserving antiplatelet therapy for established cardiovascular or neurovascular indications.

Remove COVID alone as an indication from order sets. Preserve antiplatelet treatment for established cardiovascular/neurovascular indications unless bleeding risk warrants review. Audit concomitant anticoagulation and major bleeding.

Bayesian adaptive platform trial; aspirin and P2Y12 arms were pooled after meeting equivalence criteria. The survival signal was secondary and did not meet the prespecified efficacy threshold. The trial excluded people at high bleeding risk; real-world bleeding could differ.

• Primary paper ↗ (opens in a new tab)
• Open full text ↗ (opens in a new tab)
• 2026 aspirin tariff ↗ (opens in a new tab)
• 2026 clopidogrel tariff ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)
• Supporting source ↗ (opens in a new tab)

150 more deaths/1,000 at 90 days (point estimate; uncertain)

Small UK RCT; no economic evaluation

Infusion and monitoring avoided; NHS price not published

Routine use would add drug acquisition, a dedicated infusion, pump/lumen time, titration and haemodynamic monitoring without demonstrated clinical or capacity benefit. A formal NHS cost analysis and trial-specific acquisition price were not published; a local budget estimate would require current pharmacy and staff costs and assume no bed-day saving.

• Drug and equipment — Not available: Landiolol acquisition price was not reported. Delivery needs an infusion pump and reliable IV access.
• Workforce — Resource input: Bedside titration plus heart-rate and blood-pressure surveillance; pharmacy preparation and governance.
• Capacity — Resource input: No proven reduction in organ support, ICU stay or hospital stay. Routine avoidance releases infusion and monitoring workload, not a proven cash saving.

Public investment

£1,278,918.60 — NIHR Efficacy and Mechanism Evaluation Programme; award 14/150/85.

Funding scope

Verified trial-specific UK award. Nominal total award shown in the NIHR Funding and Awards record; no inflation adjustment The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.279 million award delivered a 40-NHS-hospital randomised evaluation in 126 patients, identified no organ-failure benefit and a concerning mortality signal, and stopped early under independent oversight. The principal return is a credible reason not to diffuse a new intravenous drug pathway in septic shock, avoiding acquisition, pump, line, titration and monitoring costs that would otherwise have been incurred without demonstrated benefit. No trial-based NHS cost-effectiveness analysis was published, so a monetary return cannot be stated reliably.

The trial changed the safety context for pharmacological heart-rate control in established septic shock and demonstrates the value of testing plausible physiological interventions before routine uptake. The finding is specific to landiolol in the studied septic-shock population and should not be extended to independent cardiac indications.

Remove routine landiolol-for-tachycardia steps from septic-shock pathways. Retain case-specific use for an independent cardiac indication, with senior review and adverse-event monitoring.

Only 126 patients were enrolled and the trial stopped early. Mortality was secondary and its confidence interval includes both little harm and substantial harm; the result does not quantify effects in other beta-blocker indications.

• Primary paper ↗ (opens in a new tab)
• Full trial report ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)
• NIHR full report ↗ (opens in a new tab)

32 fewer 90-day deaths/1,000 (point estimate; threshold not met)

Bayesian platform RCT; economics not published

Low-cost drug, but extra safety monitoring and adverse events

Generic simvastatin is inexpensive, but a pathway still needs medicines reconciliation, enteral administration and liver-enzyme/creatine-kinase surveillance. There is no published UK cost-effectiveness analysis, and the eligible population has changed substantially; no UK cost-effectiveness case for routine procurement was identified.

• Drug — Not available: Simvastatin 80 mg daily; a current NHS acquisition price was not reported in the trial.
• Monitoring — Resource input: Medication interactions, hepatic enzymes and creatine kinase; enteral administration in critically ill patients.
• Capacity — Resource input: Reported ICU/hospital medians favoured simvastatin, but competing mortality and time-to-discharge analyses prevent treating median differences as cashable bed-days.

Public investment

Not publicly verified — International public and charitable consortium, including NIHR and the NIHR Imperial Biomedical Research Centre, EU PREPARE and RECOVER, Australian NHMRC and MRFF, CIHR, Health Research Board Ireland and Wellcome; funding reference/scope Multiple platform awards; no single simvastatin-domain award reference.

Funding scope

Funding sources verified; trial-domain amount not publicly verified. The paper lists multiple platform and national awards but does not allocate a consolidated amount to this domain The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The shared REMAP-CAP infrastructure enrolled 2,684 critically ill patients into the simvastatin comparison and generated a rapid international estimate for a repurposed, inexpensive medicine. The domain did not cross its prespecified superiority threshold and identified more serious adverse events, preventing a suggestive Bayesian probability from being mistaken for definitive evidence. A simvastatin-specific grant denominator is unavailable, so a monetary return or cost per participant would be artificial.

The trial illustrates the value of reusable adaptive-platform infrastructure: governance, sites, randomisation and analysis supported several treatment questions rather than a single stand-alone study. It also produced safety evidence relevant to drug-interaction and liver- and muscle-toxicity monitoring, while the changing COVID-19 population limits direct present-day service impact.

Do not add routine ICU-COVID simvastatin order sets. Preserve ordinary cardiovascular indications and consider future evidence synthesis rather than treating a 95.9% probability as having crossed the trial’s 99% rule.

Recruitment closed as COVID-19 cases fell, not at a prespecified efficacy boundary. The 90-day interval includes no effect and the contemporary population, variants and co-treatments differ.

• Primary paper ↗ (opens in a new tab)
• Full paper ↗ (opens in a new tab)
• Paper funding statement ↗ (opens in a new tab)
• NIHR platform summary ↗ (opens in a new tab)

113 fewer deaths/1,000 if REBOA is avoided (uncertain)

UK Bayesian RCT + NIHR economic model

£1,825 device cost avoided per case (2022)

Deimplementation avoids a £1,825 device per treated patient in 2022 prices—£182,500 for every 100 uses—plus training, credentialling, stock and governance. The formal model found REBOA cheaper only because more patients died earlier; that is not a legitimate efficiency gain.

• Device — Resource input: £1,825 per participant (2022 supplier price). This excludes current inflation, local packs, wastage, training and service readiness.
• Workforce — Resource input: Competency maintenance, simulation, governance and immediate trauma-team coordination. The economic model assumed no additional staff, so it may understate implementation cost.
• Economic interpretation — Resource input: REBOA had >99% probability of lower lifetime cost but 91% probability of fewer QALYs because death occurred more often and earlier. Do not describe this as a saving.

Public investment

£1,251,354.07 — NIHR Health Technology Assessment Programme; award 14/199/09.

Funding scope

Verified trial-specific UK award. Nominal total award shown in the NIHR Funding and Awards record; April 2017 to March 2023 The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.251 million award produced the first randomised evaluation of emergency-department REBOA, including 90 patients at 16 UK major trauma centres, prespecified Bayesian stopping for harm, six-month follow-up and a lifetime NHS economic model. It supplied the evidence needed to halt routine diffusion of a £1,825-per-use device in the tested setting and avoid continuing training, stock and governance investment without benefit. The full value is larger than device acquisition alone because the trial identified possible mortality harm; no counterfactual uptake estimate exists from which to calculate cash return.

UK-REBOA is a strong evidence-before-diffusion case study for invasive devices. It supports active surveillance, competency governance and early stopping in emergency research, and protects limited trauma-team training time for interventions that accelerate definitive haemorrhage control.

Remove routine REBOA activation, procurement and performance metrics for this indication; preserve research or exceptional governance routes. Track device use and redirect training time to rapid definitive haemorrhage control.

Only 90 patients were randomised and the credible interval is broad. The 113-per-1,000 figure is a point estimate, not a guaranteed number of lives saved. Price is historical and supplier-derived.

• Primary paper ↗ (opens in a new tab)
• NIHR scientific summary ↗ (opens in a new tab)
• Costs and device price ↗ (opens in a new tab)
• Lifetime model ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)
• NIHR full report ↗ (opens in a new tab)
• Clinical and economic summary ↗ (opens in a new tab)

Similar function; 83 fewer wound complications/1,000

International RCT + UK economic evaluation

Craniotomy saved £5,520/patient on average (UK model)

Craniotomy avoids many planned cranioplasties and reduced wound complications, while accepting more early additional cranial operations. In the UK economic cohort it was £5,520 less costly per patient on average and gained 0.093 QALYs, with an 87% probability of cost-effectiveness at £20,000/QALY.

• Index surgery — Resource input: Both strategies require emergency theatre and neurocritical care; craniotomy replaces the bone flap during the index operation.
• Downstream — Resource input: Decompressive craniectomy usually creates a later cranioplasty pathway, implant/bone-flap handling, theatre admission and complication exposure.
• Budget scenario — Resource input: At the published point estimate, 100 feasible cases shifted to craniotomy imply £552,000 lower mean 12-month cost; the CI spans extra cost, so use local case volume and sensitivity analysis.

Public investment

£1,216,179.16 — NIHR Health Technology Assessment Programme; award 12/35/57.

Funding scope

Verified trial-specific UK award. Nominal total award shown in the NIHR Funding and Awards record; no inflation adjustment The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.216 million award supported 450 randomised patients across 40 centres in 11 countries and a prespecified UK economic evaluation. It resolved a common operative choice: where the bone flap can safely be replaced, craniotomy achieves similar functional outcome, fewer wound complications and avoids much of the later cranioplasty pathway. The UK analysis estimated £5,520 lower 12-month cost and 0.093 more QALYs per patient; at that point estimate roughly 221 eligible cases would equal the grant value, but the cost confidence interval crossed zero, so this is scenario arithmetic rather than a guaranteed payback.

The evidence can reduce repeat theatre admissions, implants or stored-bone pathways, wound complications and disruption for patients and families. Its international neurosurgical network and pragmatic intraoperative randomisation also provide a model for evaluating emergency surgical decisions, including in settings where later cranioplasty access is constrained.

Update neurosurgical guidance and consent language: replace the flap when intraoperative swelling permits, record reasons when it cannot be replaced, and audit early reoperation, cranioplasty and wound complications.

The economic analysis used 248 UK participants and has wide cost uncertainty. Patients whose brain was too swollen for replacement were not randomised, so the recommendation is conditional on operative feasibility.

• Primary paper ↗ (opens in a new tab)
• UK economic evaluation ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)
• NIHR Cambridge impact summary ↗ (opens in a new tab)

11 fewer 90-day deaths/1,000 (point estimate)

UK RCT + NIHR economic evaluation

£2,143 lower 30-day mean cost/patient (published)

This is a protocol change using existing monitors, not a new device. The published 30-day mean cost was £2,143 lower per child (95% CI £4,320 lower to £34 higher). At one year the estimate was £879 lower but highly uncertain; implementation would chiefly require education, alarm/target changes and audit.

• Capital and consumables — Resource input: No new monitor or oxygen-delivery device is required; oxygen use may fall, but acquisition savings were not separately reported.
• Implementation — Resource input: Protocol education, revised bedside targets/alarms, escalation criteria and compliance audit across PICU and transport teams.
• Capacity — Resource input: Published short-term costs favoured conservative targets. Do not convert the composite rank result or survivor medians into national bed-days without patient-level means.

Public investment

£1,567,376.00 — NIHR Health Technology Assessment Programme; award NIHR127547 (legacy project reference 12/75/47).

Funding scope

Verified trial-specific UK award. Nominal total award shown in the NIHR Funding and Awards record; no inflation adjustment The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The £1.567 million award randomised 2,040 children across 15 NHS paediatric ICUs and associated transport services and included clinical and economic follow-up. NIHR's scale-up estimate is 50 additional survivors, 6,000 fewer ICU bed-days and £20 million lower NHS cost each year; if realised, one year's projected saving is about 12.8 times the original award. This is a national extrapolation, not cash directly observed in the trial, and implementation and exception-pathway costs remain. A further £257,141 NIHR award is supporting longer-term neurodevelopmental follow-up, extending the value of the cohort.

The intervention needs no new device and may reduce oxygen use, organ-support intensity and alarm-driven escalation. NIHR has highlighted potential relevance to settings with constrained medical-oxygen supply and to health inequalities because critical illness disproportionately affects deprived communities. The follow-on neurodevelopment study addresses whether short-term benefit is maintained without later developmental harm.

Embed the target in PICU ventilation charts and electronic orders, define exceptions, monitor hypoxaemia and protocol adherence, and avoid using the result for non-ventilated or elective populations not studied.

The clinical effect is small, two large PICU populations were excluded for lack of equipoise, and one-year cost/QALY intervals are wide. Monetary figures retain their study price year.

• Primary paper ↗ (opens in a new tab)
• NIHR trial and economic report ↗ (opens in a new tab)
• Long-term economic analysis ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)
• NIHR impact estimate ↗ (opens in a new tab)
• NIHR Evidence wider-impact summary ↗ (opens in a new tab)
• Follow-on award ↗ (opens in a new tab)

54 fewer unfavourable neurological outcomes/1,000 (uncertain)

International RCT; no UK economic evaluation

About 3.2 extra red-cell units/patient with liberal strategy

The liberal strategy used roughly 3–4 additional red-cell units per patient without a definitive neurological or mortality benefit. For 1,000 patients this is about 3,200 extra units before laboratory, storage, administration, observation and reaction costs—material blood-supply and workforce demand.

• Blood components — Resource input: Approximately 3.2 extra red-cell units per patient. Use the current NHS Blood and Transplant component price, not an old literature price.
• Delivery — Resource input: Group-and-screen/crossmatch, cold-chain inventory, portering, bedside checks, administration and reaction surveillance.
• Opportunity cost — Resource input: Extra units may constrain a shared blood supply. No trial-based UK QALY or downstream rehabilitation-cost analysis was published.

Public investment

Not publicly verified — Canadian Institutes of Health Research Project and Foundation grants, with Canadian Accelerating Clinical Trials Consortium support; award PJT 148934; FDN 148443.

Funding scope

Funding and references verified; trial-specific amount not publicly verified. The publications identify the awards but do not state the trial-specific or consolidated amount; the Foundation award also supports a wider research programme The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The funding supported a 742-participant trial across 34 centres in Canada, the United Kingdom, France and Brazil, with six-month functional and quality-of-life follow-up. It replaced practice variation and biological uncertainty with a precise estimate: a routine liberal threshold did not significantly improve the primary neurological outcome and used roughly 3.2 additional red-cell units per patient. A monetary return cannot be calculated because neither a trial-specific grant total nor a UK economic evaluation is public.

The result affects donor-blood demand, transfusion-laboratory workload, bedside checks and reaction surveillance as well as acquisition cost. It supports conserving a shared blood supply unless patient-specific cerebral oxygenation, bleeding or comorbidity justifies a different threshold, while preserving uncertainty about a possible functional benefit for future synthesis.

Keep a restrictive default with explicit exceptions and shared neurocritical care/transfusion review. Audit red-cell units, haemoglobin exposure, cerebral-ischaemia signals, ARDS and neurological outcomes.

The confidence interval contains both no benefit and a substantial functional benefit. Per-1,000 red-cell use is calculated from reported group averages and does not include wastage or transfusion reactions.

• Primary paper ↗ (opens in a new tab)
• Full paper ↗ (opens in a new tab)
• Trial protocol and funding references ↗ (opens in a new tab)

880 antibiotic-days avoided/1,000; mortality non-inferior

UK RCT + NHS/PSS economic evaluation

About £92 extra/patient in conservative UK costing

PCT shortened antibiotic exposure by 0.88 day per patient but adds daily testing. The UK economic analysis estimated £15.20 per PCT test and, when only proven test/antibiotic differences were counted, about £92 additional cost per patient; downstream antimicrobial-resistance value was not captured.

• Laboratory — Resource input: Daily PCT assay, sample collection/transport, analyser capacity and result turnaround; the economic model used £15.20/test.
• Stewardship workforce — Resource input: Protocol education, daily review and authority to stop antibiotics. Testing without timely action creates cost without benefit.
• Economic range — Resource input: Within-trial full model was dominated because uncertain mortality/stay point estimates drove cost; meta-analysed lifetime model estimated £284 extra and 0.139 QALY, ICER £2,053/QALY. Treat this divergence as uncertainty.

Public investment

£2,070,222.09 — National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme; award 15/99/02.

Funding scope

Verified. Total award value shown by NIHR; nominal pounds, price year not stated. NIHR128374 for the embedded mechanistic study and NIHR Clinical Research Network infrastructure support are additional and are not included in this total. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The main award delivered a 2,761-participant, three-group randomised trial across 41 UK critical care units, together with an NHS/PSS economic evaluation and an embedded mechanistic programme. It resolved two stewardship questions in one study: daily procalcitonin guidance reduced antibiotic exposure, whereas the tested daily C-reactive-protein protocol did not. The main award equates to approximately £750 per randomised participant (award divided by recruitment only; this is a descriptive delivery indicator, not a cost-effectiveness ratio). The economic work also showed why implementation decisions depend on assay cost, protocol adherence and how antimicrobial-resistance benefits are valued.

The study supplies UK-specific evidence for antimicrobial stewardship and reduces uncertainty around two biomarkers already available in many hospitals. Its potential system value includes fewer antibiotic doses and less selection pressure for antimicrobial resistance, balanced against extra phlebotomy, laboratory throughput, reagents and staff time for daily procalcitonin testing. Resistance, environmental and laboratory-capacity effects were not fully monetised, so they should be described as plausible but unquantified rather than claimed as cash savings.

Link PCT results to an antimicrobial-stewardship stop algorithm and clinician override documentation; monitor tests per patient, antibiotic-days, restart, mortality and laboratory turnaround. Do not substitute daily CRP, which did not reduce duration.

The safety CI approaches the non-inferiority margin and the economic conclusion changes when uncertain mortality effects are included. Resistance benefits are plausible but unquantified; local test contracts and baseline antibiotic duration drive budget impact.

• Primary paper ↗ (opens in a new tab)
• Economic evaluation ↗ (opens in a new tab)
• Open economic full text ↗ (opens in a new tab)
• JAMA article and funding statement ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)

7 more 90-day deaths/1,000 (95% CI 7 fewer to 20 more)

Large UK RCT; economics not published

29% less supplemental oxygen; no stay/capacity benefit

Conservative therapy reduced supplemental oxygen exposure by 29%, which may reduce cylinder/oxygen-plant demand in some settings, but the trial did not publish oxygen quantities or a monetary analysis. No ICU/hospital capacity saving was demonstrated.

• Technology — Resource input: Uses existing ventilators, oxygen supply and oximetry; no new capital device.
• Implementation — Resource input: Target/alarms, staff education, FiO₂ titration and hypoxaemia surveillance. A narrower target may increase bedside adjustment.
• Potential saving — Resource input: Oxygen consumption fell, but savings depend on marginal oxygen source (piped bulk versus cylinders) and were not costed. Do not infer hospital-day savings.

Public investment

£1,724,102.40 — National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme; award NIHR130508.

Funding scope

Verified. Total award value shown by NIHR; nominal pounds, price year not stated. The value does not separately price ICNARC's established audit infrastructure or wider NIHR delivery support. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The award delivered a 16,500-participant trial in 97 UK ICUs with 90-day mortality available for 16,394 participants. This is approximately £104 per randomised participant (award divided by recruitment only; not a cost-effectiveness ratio), reflecting the leverage obtained from a pragmatic, registry-embedded design and linkage to routinely collected data. The trial provided a precise national answer that the tested conservative oxygen target did not improve mortality, organ-support-free days or length of stay, while reducing supplemental oxygen exposure by 29%. The integrated economic evaluation was planned but had not been published with the primary report.

UK-ROX is an important demonstration that an established national audit and data-linkage system can support a very large critical care trial at comparatively low marginal cost. Clinically, it prevents a blanket lower-saturation target being justified by presumed mortality or capacity benefit while retaining the broader principle of avoiding unnecessary hyperoxaemia. Lower oxygen exposure could reduce oxygen production, storage or cylinder logistics in some settings, but quantities, marginal costs and environmental effects were not reported and should not be presented as established savings.

Do not impose a universal low-oxygen protocol. Preserve sensible oxygen stewardship, define patient-specific exceptions and monitor severe hypoxaemia/serious adverse events if local targets change.

The interval excludes a large benefit but includes small harm or benefit. Oxygen exposure reduction is a resource input, not proof of cost-effectiveness; current unit costs and delivery infrastructure vary.

• Primary paper ↗ (opens in a new tab)
• Open full text ↗ (opens in a new tab)
• JAMA article and funding statement ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)
• ICNARC trial record ↗ (opens in a new tab)

52 more 90-day deaths/1,000 (unadjusted point estimate)

International Bayesian RCT stopped for futility

28 IV doses plus monitoring avoided; acquisition price not reported

A full course requires 28 IV 50-mg doses, repeated preparation/administration and glucose/infection surveillance. The arm stopped for futility and had a high posterior probability of harm, so routine use would add workload without a demonstrated outcome return.

• Drug — Not available: Hydrocortisone 50 mg IV every 6 hours for seven days (28 doses). Trial-specific UK acquisition cost was not reported.
• Workforce — Resource input: Pharmacy/nursing preparation and administration, glucose/insulin management and infection/delirium/neuromuscular monitoring.
• Capacity — Not available: No demonstrated mortality or length-of-stay benefit. Avoidance releases medication workload but no formal cash or bed-day estimate is available.

Public investment

Not separately attributable to this comparison — Multiple international platform funders, including EU PREPARE, RECOVER and ECRAID-Base programmes, the UK NIHR and Imperial College Healthcare NHS Trust Biomedical Research Centre, and national funders in Australia, New Zealand, Canada, Ireland, France, Singapore and the USA; funding reference/scope Platform awards include EU 602525, 101003589 and 965313; the paper does not identify a discrete award for this hydrocortisone comparison.

Funding scope

Verified platform funding; trial-specific amount not publicly separable. REMAP-CAP platform funding supported multiple regions, domains and time periods. Neither the paper nor a public funder record separates the cost of the fixed-duration hydrocortisone comparison, so a trial-specific grant total or grant-per-participant figure would be misleading. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

A conventional grant-return calculation is not valid for this comparison because the international platform reused shared governance, sites, data systems and Bayesian statistical infrastructure across many treatment domains. Within that platform, 658 patients were randomised to fixed-duration hydrocortisone or control at 101 sites in 18 countries. The arm crossed a prespecified futility boundary and recruitment stopped, limiting further exposure to a regimen unlikely to produce a large mortality reduction. The return is therefore both the clinical answer and the reusable platform capacity; it cannot honestly be assigned to one UK grant amount.

The study illustrates a major advantage of an adaptive platform: a treatment arm can stop when a prespecified decision rule is met while the platform continues to answer other questions. It contributes internationally generalisable evidence and preserves research readiness for pandemic and interpandemic pneumonia. Its conclusion is specific to a fixed seven-day hydrocortisone course in this population; it should not be generalised to every corticosteroid, regimen, timing or septic-shock indication, particularly given differing results from other severe-pneumonia steroid trials.

Do not add a blanket severe-CAP seven-day order set. Keep separate pathways for refractory septic shock and any guideline-supported alternative steroid regimen; document indication and stop date.

Only 122 controls and 15 missing 90-day outcomes; credible intervals allow smaller benefit or harm. The conclusion is regimen- and population-specific and should be reconciled with other severe-CAP steroid evidence.

• Primary paper ↗ (opens in a new tab)
• Open full text ↗ (opens in a new tab)
• Publisher article page ↗ (opens in a new tab)
• Publisher correction to institutional authorship ↗ (opens in a new tab)
• REMAP-CAP platform funding context ↗ (opens in a new tab)

No faster liberation; 12 extra GI bleeds and 38 extra hypoxaemia events/1,000

UK factorial RCT; economic evaluation pending

Avoid up to 84 enteral doses or 112 nebulisations/patient

Stopping routine use removes drug purchase and substantial administration workload: carbocisteine three times daily or hypertonic saline four nebulisations daily for up to 28 days. Exact NHS cost-effectiveness results were not yet available, but the clinical case supports deimplementation before monetisation.

• Maximum delivery burden — Resource input: Up to 84 enteral carbocisteine doses or 112 nebulised HTS doses per patient over 28 days, plus pharmacy/stock and documentation.
• Equipment and staff — Resource input: Nebuliser/interface, respiratory and nursing time, circuit interruption/aerosol precautions; enteral preparation/administration for carbocisteine.
• Avoided harm — Resource input: Bleeding assessment/treatment, bronchodilator use and hypoxaemia response. Current drug and staff prices plus the integrated economic analysis are needed for cash estimates.

Public investment

£2,149,636.50 from NIHR; Belfast charitable award amount not stated — National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme; additional Belfast Health and Social Care Trust Charitable Trust Fund support; award NIHR130454; Belfast charitable award J-2425-505.

Funding scope

NIHR amount verified; additional charitable amount not publicly verified. NIHR total award value shown by the current NIHR Funding and Awards record; nominal pounds, price year not stated. The separately acknowledged charitable award is additional but its value is not publicly stated in the paper. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The NIHR award delivered a 1,956-participant 2×2 factorial trial, efficiently answering two routine-treatment questions within one trial infrastructure. It found no reduction in mechanical ventilation duration with carbocisteine or nebulised hypertonic saline and identified clinically important harms with each treatment. The NIHR award is approximately £1,099 per randomised participant (award divided by recruitment; not a cost-effectiveness ratio and excluding the additional charitable award). The factorial design increases the informational return because two treatments were tested contemporaneously; the integrated economic evaluation should be added when published.

MARCH provides a direct basis for reviewing routine mucoactive prescribing, nebuliser stock and ventilator secretion protocols. Deimplementation can release pharmacy and nursing time and avoid repeated enteral doses or nebulisations, circuit handling and treatment-related adverse events. It may also reduce medicine, syringe and nebuliser waste and aerosol-generating activity, but the trial did not report a lifecycle or environmental analysis. The result does not preclude carefully justified patient-specific use outside the population and indications tested.

Remove routine mucoactive defaults from ventilator secretion pathways; retain case-specific indications outside the trial question, use non-pharmacological secretion management and audit residual use and adverse events.

The trial was open label and treatment duration varied. Differences between ventilation medians are not additive resource totals. The planned economic evaluation should be added when published.

• Primary paper ↗ (opens in a new tab)
• Full paper ↗ (opens in a new tab)
• NIHR trial record ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)

No worse ventilation/survival; 153 fewer feed stops/1,000

UK/Swiss non-inferiority RCT; economics pending

Up to four nursing checks/day and disposables released

This is a deimplementation intervention: no new device or drug. It can release repeated nursing time, syringes/containers and documentation and reduces feed interruption. Exact staff minutes, disposable cost and downstream economic results were not published with the primary paper, so local savings require time-and-motion data.

• Routine task removed — Resource input: Usual care assessed GRV at least every six hours: up to four aspirations, measurements and records per child-day.
• Consumables and workforce — Published economic analysis: Enteral syringes/containers, PPE, bedside nursing time and documentation; exact quantities and unit costs await the integrated health economic evaluation.
• Capacity — Resource input: No ventilation-duration or survival gain should be claimed. Value is released staff time, fewer feed interruptions and better early nutrition, not proven PICU bed-days.

Public investment

£2,021,458.74 from NIHR; Swiss foundation amounts not stated — National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme; Swiss participation supported by the NOMIS Foundation and Thomas and Doris Ammann Foundation; award NIHR133835.

Funding scope

NIHR amount verified; additional Swiss amounts not publicly verified. NIHR total award value shown by NIHR; nominal pounds, price year not stated. The value of the separately acknowledged Swiss support is not publicly stated in the primary paper. The award value is not assumed to equal the marginal cost of this comparison.

What the investment delivered

The NIHR award delivered a 4,700-child pragmatic non-inferiority trial in 23 UK PICUs and one Swiss PICU, with 4,460 children in the primary intention-to-treat analysis. The award is approximately £430 per randomised child (NIHR award divided by total recruitment; a descriptive indicator only, excluding Swiss support and not a cost-effectiveness ratio). It produced high-powered evidence that omitting routine gastric-residual-volume assessment was not inferior for survival and ventilator-free days and improved early nutritional delivery. It therefore answers a widespread nursing-practice question without requiring a new technology; the embedded economic evaluation remains important for converting released task time and consumables into defensible local savings.

This is deimplementation evidence with potential to remove up to four routine aspirations and records per child-day, release bedside nursing time, reduce syringes and other consumables, and prevent feed interruption. The trial also supports nutrition quality improvement and provides internationally relevant paediatric evidence without showing a PICU length-of-stay benefit. Any workforce or environmental saving should be estimated locally because the primary paper did not report task minutes, unit costs or a lifecycle assessment. Implementation should preserve clinical assessment and explicit rescue indications rather than treating ‘no routine measurement’ as ‘no assessment of feed intolerance’.

Delete six-hourly GRV from default charts, train staff in clinical intolerance signs and explicit rescue indications, monitor vomiting/aspiration/VAP/NEC, nutritional delivery and protocol crossover.

Non-inferiority depends on the prespecified margin and protocol adherence. Fifteen per cent of intervention children still had at least one non-protocol GRV check; exact economic savings are pending and will vary with nursing workflow.

• Primary paper ↗ (opens in a new tab)
• Full paper ↗ (opens in a new tab)
• Economic protocol ↗ (opens in a new tab)
• NIHR award record ↗ (opens in a new tab)
• Trial and economic-evaluation protocol ↗ (opens in a new tab)