Hypothermia Research Register
Research register · frozen 10 August 2026
One corpus. Different levels of evidence.
Hypothermia is not a single intervention. Population, timing, target temperature, duration, route, comparison treatment, spatial distribution and rewarming determine what a study actually tests. This register uses positive, neutral and negative results together to sharpen the next protocol, identify the most testable AIRCHILL path and turn uncertainty into explicit study objectives.
33,808records in the machine-curated source register
32,462deduplicated PubMed records in the research corpus
1,331unique ClinicalTrials.gov studies in the register collection
2,174high screening-priority records
60sources manually included and documented for claims
How to read this site
Evidence is a ladder, not a pile.
A large database does not turn metadata into clinical proof. The same trial can appear as a protocol, registry entry, primary report, follow-up and secondary analysis. Medical Cooling therefore separates six statement types.
Mechanism
Biology is plausible
A measurable physical or biological process occurs. It can justify the next experiment, but not a patient-benefit claim.
Feasibility
The procedure can be delivered
A method can be performed under the tested conditions. Feasibility is not efficacy.
Safety signal
Limited data define a risk picture
The absence of a problem in a small cohort is not a general safety proof.
Clinical benefit
Patient-relevant outcomes improve
Requires a design capable of supporting the specific claim in the specific population.
Clinical validation target
The evidence defines the next study
An unresolved question becomes a prospective objective: specify the population, thermal exposure, safety gate and endpoint needed to test and size the effect.
Design information
A neutral result improves the next protocol
Neutral findings narrow the relevant route, population, timing, dose or endpoint and help design a more informative prospective test.
Thermal dose
Temperature is not a number. It is a controlled trajectory.
The research synthesis treats therapeutic temperature as a multidimensional dose. Two trials that both say “33 °C” can still deliver very different interventions.
DepthHow far the target temperature is lowered.
SpeedWhen cooling begins and how quickly the intended target is reached.
DurationHow long tissue remains inside the defined therapeutic range.
DistributionWhich organ or region is actually cooled, and how uniformly.
RewarmingHow controlled the intervention ends and fever is prevented afterwards.
AIRCHILL implication. A future programme cannot be judged by “cold gas” or a single temperature reading. It needs reproducible heat removal, validated target-organ or surrogate measurement, airway and pulmonary safety, stable ventilation, a controlled end to exposure and a patient-relevant comparison.
Clinical evidence map
Where hypothermia stands by indication.
| Field | Status | What the evidence supports | What it does not support |
|---|---|---|---|
| AIRCHILL | Preclinical / exploratory | Local temperature change; early technical feasibility under defined experimental conditions. | Patient safety, sufficient organ or whole-body cooling, clinical benefit. |
| Cardiac arrest | Temperature control established | Protocolised temperature management and fever control; current target choice remains context-dependent. | Universal superiority of 33 °C; benefit of large cold-fluid boluses; benefit of simply extending 33 °C duration. |
| Transnasal intra-arrest cooling | Efficacy open | Earlier temperature reduction; PRINCESS2 pilot supports protocol feasibility. | Established clinical benefit or transfer to AIRCHILL. |
| Neonatal HIE | Established in a narrow indication | Protocolised whole-body hypothermia in carefully selected term / near-term neonates with moderate-to-severe HIE in the early treatment window. | Routine extension to mild HIE, younger preterm infants or late treatment without new evidence. |
| Ischaemic stroke | Experimental | Feasibility; heterogeneous signals; selective approaches are under active study. CHILL-ART currently remains a conference-level result in this corpus. | Established standard, proven mortality reduction or equivalence of local and systemic methods. |
| Severe TBI | No general benefit established | Hypothermia can lower intracranial pressure in some settings. | Improved functional outcome from general prophylactic or systemic hypothermia. |
| Spinal cord injury | Experimental | Preclinical plausibility and small feasibility signals. | Established clinical efficacy. |
| Accidental hypothermia | Rewarming / resuscitation medicine | Continued resuscitation in appropriate cases and extracorporeal support / rewarming in selected patients. | One universal randomized effect estimate for every rewarming strategy. |
| Perioperative hypothermia | Prevention established | Active warming and prewarming can reduce perioperative hypothermia and shivering. | Transfer of warming evidence to therapeutic neuroprotection. |
| Sepsis / ARDS | Open | Controlled programmes are testing fever control and hypothermia. | Clinical benefit before results are available. |
Trial register
What the next generation of studies is testing.
Status below is a frozen research snapshot. A registry entry describes planning and status, not efficacy. Completion dates can become stale and publications can appear before registry result tables are updated.
| Study | Field | Status | n | Planned / reported completion | What it addresses | Gewonnenes Wissen |
|---|---|---|---|---|---|---|
| CLARINET · NCT07220928Cold-air eucapnic hyperventilation airway study | Cold-air safety | Completed · no posted results | 60 actual | Completed 2024-11-27 | Healthy adults and mild-to-moderate asthma; standardized −15 °C cold-air challenge vs room-temperature EVH; FEV1, symptoms, small-airway function, sputum/blood inflammation and epithelial-integrity markers. | Directly relevant safety architecture: combine mechanics, symptoms, local/systemic inflammation and epithelial integrity. Registry existence proves the study, not a positive safety result; results were not posted in the record reviewed 23 Aug 2026. |
| CLARINET2prospective follow-on described in CLARINET registry | Cold-air safety | Planned · separate registry not verified | NR | NR | Planned prospective diagnostic validation of the optimized cold-air protocol. | Track as a planned study only. Do not label recruiting/ongoing until a public registry entry is verified. |
| ICECAP · NCT04217551Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients | Cardiac arrest | Active, not recruiting | 1,158 actual | Primary completion listed 2025-09-05 | Adaptive duration/dose-finding comparison of therapeutic hypothermia with weighted 90-day mRS as primary outcome. As of the current ClinicalTrials.gov record, no results are posted. | Duration is a separate causal question from target, timing and route. AIRCHILL should reconstruct onset, depth, cooling rate, duration and rewarming independently and should not cite an unpublished ICECAP outcome. |
| P-ICECAP · NCT05376267 | Cardiac arrest | Recruiting | 900 estimated | 2028-03-31 | Cooling duration after paediatric cardiac arrest. | Paediatric arrest is not an adult surrogate. A separate population, physiology, consent pathway and outcome model are required; AIRCHILL should not transfer adult assumptions into paediatric development. |
| PRINCESS2 · NCT06025123 | Cardiac arrest | Recruiting | 1,022 estimated | 2028-05 | On-scene transnasal cooling in initially shockable OHCA; pilot addressed adherence and device-related safety, not efficacy. | The programme learned from PRINCESS by narrowing to an initial shockable rhythm, separating a 100-patient feasibility/adherence pilot from efficacy, and powering the main trial for a prespecified 9-point absolute difference. For AIRCHILL, phenotype, timing, adherence and safety should be proven before a pivotal outcome claim. |
| NCT06776549 | Cardiac arrest | Recruiting | 468 estimated | 2030-01-31 | Hypothermia versus normothermia after ECPR for OHCA. | ECPR should be treated as a distinct study stratum because its workflow and timing differ materially from conventional resuscitation. |
| OverCool · NCT06798818 | Cardiac arrest | Not yet recruiting in snapshot | 24 estimated | 2026-03 | Ultra-rapid cooling induction using total liquid ventilation; small feasibility programme. | A very small study can be appropriate when the question is technical feasibility rather than clinical benefit. AIRCHILL should use early cohorts to establish deliverability and safety, not to infer neurological efficacy from a handful of patients. |
| NCT07086703 | Cardiac arrest | Not yet recruiting | 788 estimated | 2029-05-01 | 33 °C versus controlled normothermia after in-hospital cardiac arrest. | In-hospital arrest differs from OHCA in delay, monitoring and cause. AIRCHILL should avoid combining fundamentally different care pathways unless interaction by setting is prespecified and adequately powered. |
| PRECEDENCE · NCT07421882 | Cardiac arrest | Recruiting | 50 estimated | 2027-03 | Small prehospital cooling-vest feasibility study. | Prehospital feasibility should quantify set-up time, treatment interruptions and achieved thermal separation. A device that is easy to deploy but produces little early temperature difference cannot answer the neuroprotection hypothesis. |
| CoolPrime · NCT04621279 | Neonatal HIE | Recruiting | 460 estimated | 2029-01-01 | Cooling versus normothermia for mild HIE. | Evidence from moderate/severe neonatal HIE does not automatically extend to mild disease. AIRCHILL should not broaden an indication merely because a related population benefits from cooling; each severity phenotype needs its own benefit–risk test. |
| COMET · NCT05889507 | Neonatal HIE | Recruiting | 426 estimated | 2030-01-01 | Whole-body hypothermia in mild neonatal encephalopathy with long-term follow-up. | Long-term outcomes require long-term follow-up. The timing of AIRCHILL endpoints should match the claimed patient benefit rather than rely only on early hospital outcomes. |
| COTTIS-2 · NCT06301412 / DRKS00031086 | Stroke | Recruiting in snapshot | 400 estimated | 2026-06-18 | Targeted temperature management integrated with thrombectomy; completion date is already past and therefore needs live re-verification before reuse. | Live status and final result sources should be re-checked before a study is used to set AIRCHILL design assumptions. |
| CHILL-ART · NCT06758609 | Stroke | Registry / publication conflict | 262 estimated | 2026-06-30 | Registry still showed recruiting while a 2026 conference abstract reported randomized results; full publication remains the higher-priority next source. | Use the final peer-reviewed report as the preferred result source when status metadata and publications conflict. |
| COOLHEAD-2b · NCT07526649 | Stroke | Not yet recruiting | 182 estimated | 2029-06-30 | Non-invasive convective head cooling during endovascular thrombectomy. | A device study should show that the intended local thermal effect is achieved during the clinically relevant procedural window before asking a patient-outcome question. |
| NCT04494074 | Sepsis | Recruiting | 820 estimated | 2026-12-01 | External fever control in mechanically ventilated septic-shock patients. | Temperature manipulation can have indication-specific effects. AIRCHILL should not transfer efficacy assumptions from post-arrest neuroprotection into inflammatory critical illness. |
| NCT04545424 | ARDS | Recruiting | 340 estimated | 2026-10-31 | Therapeutic hypothermia in ARDS. | Pulmonary disease changes the safety question. For AIRCHILL, respiratory indications require separate gas-exchange and lung-safety evidence rather than borrowing from neurological indications. |
| NCT02991690 | Spinal cord | Recruiting | 120 estimated | 2026-09 | Systemic hypothermia after acute cervical spinal cord injury. | Mechanistic plausibility in another nervous-system injury does not establish transferability. Each AIRCHILL indication needs its own population, timing window and patient-relevant endpoint. |
| NCT06200285 | Accidental hypothermia | Recruiting registry | 500 estimated | 2054-12 | International observational registry; not a randomized intervention. | Observational registries are valuable for incidence, safety patterns and prognosis, but they cannot substitute for randomized evidence when estimating an AIRCHILL treatment effect. |
Register snapshot: ClinicalTrials.gov API v2 data state 7 August 2026, research extraction 10 August 2026. Status is intentionally shown with conflicts instead of silently overwriting them.
Publication lessons
Why earlier cooling studies were positive, neutral or inconclusive.
A neutral trial is not automatically “too small”. The decisive question is whether the study created the biological contrast it intended, in the right population, early enough, with an endpoint and sample size capable of detecting a realistic effect. Post-hoc and subgroup findings are labelled as such and are not treated as confirmatory evidence.
| Publication / study | N | What was tested | Result / why interpretation is difficult | Gewonnenes Wissen |
|---|---|---|---|---|
| PRINCE · 2010Circulation | ~200 randomized | Intra-arrest transnasal evaporative cooling during CPR. | Cooling was clearly accelerated, but the pilot was not powered for patient-relevant clinical outcomes. | A small randomized device study can establish feasibility and thermal separation; it should not be used to estimate a stable neurological effect size for a pivotal trial. |
| PRINCESS · 2019JAMA | 677 randomized; 671 completed | Transnasal intra-arrest cooling versus standard care in a broad witnessed OHCA population. | Core temperature <34 °C was reached earlier (median 105 vs 182 min), but CPC 1–2 at 90 days was 16.6% vs 13.5% (absolute difference 3.1 points; 95% CI −2.3 to 8.5). The primary endpoint was neutral. | The study was not simply “negative because too small”: the observed overall effect was much smaller than a large pivotal-effect assumption, and the population mixed prognostically different rhythms. AIRCHILL should prespecify phenotype and power to a conservative effect, not to a post-hoc signal. |
| TTM · 2013NEJM | 939 primary analysis | 33 °C versus actively controlled 36 °C after OHCA. | No mortality or neurological advantage of 33 °C. Both groups received protocolised temperature control, so the comparison was not cooling versus uncontrolled fever. | Comparator quality matters. If both arms receive effective temperature management, the incremental effect can be small. AIRCHILL must define what physiological contrast it adds on top of modern standard care. |
| Kim et al. · 2014JAMA | 1,359 randomized | Up to 2 L of 4 °C saline immediately after ROSC versus standard care. | Hospital temperature was lowered and target was reached about an hour earlier, but survival and neurological status did not improve; the fluid strategy also added a treatment burden distinct from selective/device cooling. | Earlier temperature reduction is not sufficient evidence of benefit if the delivery method introduces competing physiological effects. AIRCHILL should separate the effect of thermal dose from fluid, pressure, ventilation or other co-interventions. |
| HYPERION · 2019NEJM | 584 randomized; 581 analysed | 33 °C for 24 h versus targeted 37 °C after nonshockable cardiac arrest. | Favourable CPC at day 90 was 10.2% vs 5.7% (difference 4.5 points; 95% CI 0.1–8.9), with no mortality difference. The signal was statistically fragile because event counts were low and the confidence interval was wide. | Low baseline event rates make binary neurological endpoints sample-hungry and unstable. AIRCHILL should obtain contemporary control-event rates before locking sample size and should avoid treating one borderline positive trial as a transferable effect estimate. |
| TTM2 · 2021NEJM | 1,900 enrolled; 1,861 ITT | 33 °C versus normothermia with early fever treatment after OHCA. | No reduction in 6-month mortality or poor functional outcome; haemodynamically important arrhythmia was more frequent with hypothermia. Median arrest-to-randomisation was about 135 min, so this trial chiefly answers later post-ROSC systemic cooling, not an intervention that produces target-organ cooling during the first minutes. | A large, well-conducted neutral trial can rule against the tested strategy without answering a materially different timing/route hypothesis. AIRCHILL must prove that it actually creates an earlier and different thermal exposure rather than cite TTM2 either for or against that untested exposure. |
| PRINCE + PRINCESS pooled analysis · 2021Critical Care | 851 as-treated; 325 initial shockable rhythm | Post-hoc pooled individual-patient analysis by initial rhythm. | Among shockable-rhythm patients, favourable outcome at discharge was 34.2% vs 24.0% (RR 1.43, 95% CI 1.01–2.02). This was post-hoc, pooled and as-treated rather than the primary randomized endpoint of either trial. | This is hypothesis-generating phenotype information, not confirmatory efficacy. It can justify prospective enrichment such as PRINCESS2, but AIRCHILL must not use the observed 10-point-plus subgroup difference as its assumed treatment effect without independent confirmation. |
| PRINCESS2 design + pilotNCT06025123 | 1,022 planned; first 100 prespecified pilot | On-scene transnasal cooling in initial shockable OHCA; mRS 0–1 at 90 days. | The programme narrowed the phenotype, created a feasibility/adherence pilot, prespecified DSMC safety/futility review and powered for an absolute 9-point difference (45% to 54%). Efficacy remains unproven while the trial is ongoing. | The strongest transferable lesson is programme architecture: qualify sites and workflow first, measure protocol adherence and real treatment timing, then run the efficacy test. The 9-point assumption belongs to PRINCESS2 and is not an AIRCHILL effect estimate. |
Interpretation rule. “Underpowered” is used only when the study was not designed to test the clinical endpoint or when its detectable effect was materially larger than the effect observed. A neutral adequately powered RCT is not rescued by a favourable post-hoc subgroup. External cooling technologies are design evidence, not AIRCHILL validation.
Clinical-development knowledge register
Each important study is converted into a reusable protocol decision record.
This register is the decision layer above the publication list. Every included study family should be appraised with the same fields so that evidence changes the next protocol rather than merely increasing the bibliography. Effect estimates remain study-specific; transferability to AIRCHILL is graded separately.
| Study | Population | Intervention / comparator | Timing & thermal dose | Patient endpoint / effect | Safety / limitations | AIRCHILL transferability | Required protocol variable / lesson |
|---|---|---|---|---|---|---|---|
| PRINCESSJAMA 2019 | Witnessed OHCA; broad arrest phenotype. | Intra-arrest transnasal evaporative cooling + standard care vs standard care. | Cooling initiated during CPR; core <34°C reached median 105 vs 182 min. | CPC 1–2 at 90 d: 16.6% vs 13.5%; +3.1 pp, 95% CI −2.3 to 8.5; neutral primary endpoint. | Broad phenotype and modest overall effect; subgroup signals post hoc. | DESIGN TRANSFER Technique and route differ from AIRCHILL. | Record treatment clocks and phenotype. Freeze initial rhythm, witnessed status, ROSC/treatment timing; do not power from post-hoc subgroup effects. |
| PRINCESS2NCT06025123 · design + 100-patient pilot | OHCA with initial shockable rhythm. | On-scene transnasal cooling vs standard care. | Very early prehospital start; intervention continued through transport / handover. | Efficacy ongoing; pilot focused on adherence and device-related safety rather than efficacy. | Pivotal effect assumption belongs to this programme only. | HIGH DESIGN RELEVANCE | Pilot before pivotal. Prespecify adherence, site qualification, transport handover, DSMC review and blinded 90-day neurological assessment. |
| TTM2NEJM 2021 · PMID 34133859 | 1,900 comatose adults after OHCA of presumed cardiac/unknown cause. | 33°C with controlled rewarming vs normothermia with early fever treatment. | Post-ROSC systemic temperature management; not intra-arrest targeted-organ cooling. | 6-mo mortality 50% vs 48%; poor functional outcome 55% vs 55%. | Haemodynamically significant arrhythmia 24% vs 17% under hypothermia. | CONTRAST BOUNDARY | Define the distinct treatment contrast. AIRCHILL must show materially earlier/different exposure and capture arrhythmia, haemodynamics, fever prevention and downstream temperature care. |
| HYPERIONNEJM 2019 | Comatose adults after non-shockable cardiac arrest. | 33°C for 24 h vs targeted 37°C. | Post-arrest systemic cooling. | Favourable CPC at day 90: 10.2% vs 5.7%; +4.5 pp; low event count. | Fragile positive signal; later combined evidence did not establish a general benefit. | HYPOTHESIS ONLY | Use contemporary control rates and prospectively defined enrichment. Do not use +4.5 pp as an AIRCHILL default. |
| COTTISESJ 2026 · PMID 41700739 | Intubated LVO stroke patients undergoing EVT. | Peri-EVT mild hypothermia vs matched standard-care controls. | Cooling integrated around thrombectomy; timing relative to reperfusion is central. | mRS 0–2: 68.2% vs 29.5%; +38.7 pp in small non-randomized matched analysis. | Very small sample; non-randomized; effect explicitly considered surprisingly large. | FEASIBILITY / SIGNAL | Randomise before/at EVT and analyse ordinal 90-day mRS. Capture anaesthesia, reperfusion time and thermal exposure; never transfer the +38.7-pp signal to sample-size planning. |
| NICHD HIENEJM 2005 · PMID 16221780 | Term / near-term neonates with moderate–severe HIE. | Whole-body hypothermia vs then-standard care. | Started within 6 h; controlled whole-body cooling for 72 h with structured rewarming. | Death or moderate/severe disability reduced from 62% to 44%. | Historical comparator; neonatal physiology and current standard care differ from adult emergency indications. | BIOLOGICAL PRINCIPLE | Biological window, dose duration and long follow-up matter. Any paediatric programme requires separate engineering and 18–24-month neurodevelopmental outcomes. |
| POLARJAMA 2018 · PMID 30357266 | Adults with severe TBI. | Early sustained prophylactic 33–35°C hypothermia vs normothermic management. | Cooling intended very early and sustained. | Favourable GOSE: 48.8% vs 49.1%; essentially no benefit. | Shows early systemic hypothermia is not generically neuroprotective in unselected severe TBI. | PHENOTYPE / ROUTE BOUNDARY | 0 pp is the evidence-aligned reference. If TBI is pursued, prospectively enrich by mechanism/phenotype and retain blinded 6-month GOSE as the patient endpoint. |
| LTH-1Contemp Clin Trials 2015 · PMID 25460339 · DOI 10.1016/j.cct.2014.11.008 | Planned 300 adults with severe TBI across 15 neurosurgical centres in China. | Long-term mild hypothermia 34–35°C for 5 days vs normothermia 36–37°C. | Long-duration exposure with standardised management; primary neurological endpoint at 6 months. | Protocol publication establishes the intended dose and outcome architecture; it is not itself an efficacy result. | Protocol-level evidence only; later outcome evidence must be appraised separately before any efficacy inference. | DOSE-ARCHITECTURE LESSON | Do not compress thermal dose into target temperature alone. Prespecify onset, duration, rewarming, ICP, complications and 6-month functional outcome; use later results—not the protocol rationale—to judge efficacy. |
| Eurotherm3235NEJM 2015 · PMID 26444221 | TBI with intracranial hypertension. | Hypothermia added to standard ICP management vs standard care. | Temperature reduction used as a tier-2 ICP-lowering treatment. | ICP fell, but clinical outcomes were worse in the hypothermia strategy. | Strong example of surrogate improvement with patient harm. | SAFETY / OUTCOME DESIGN | Never substitute physiology for outcome. Capture GOSE/mortality plus rewarming, infection, bleeding, haemodynamics and other co-interventions. |
| Exertional heat-stroke CWIDeMartini et al. · PMID 24983342 | 274 exertional heat-stroke cases treated on site. | Immediate cold-water immersion; no randomized AIRCHILL-like comparator. | Mean initial rectal temperature ~41.4°C; mean cooling rate 0.22°C/min. | 100% survival in this cohort. | Observational cohort; CWI is a distinct established modality and cannot yield an AIRCHILL survival effect. | PROCESS BENCHMARK | Use thermal performance first. Early heat-stroke feasibility should measure °C/min, time to <40°C / target range, time above dangerous temperature, organ-failure trajectory, workflow and safety against best rapid cooling. |
| TTMNEJM 2013 · PMID 24237006 | 950 unconscious adults after OHCA of presumed cardiac cause; 939 in primary analysis. | 33°C vs actively controlled 36°C. | Both arms received protocolised temperature control and fever prevention. | No significant mortality or neurological advantage at 33°C. | Comparator quality reduces the incremental treatment contrast. | COMPARATOR LESSON | Define what AIRCHILL adds to modern care. Record downstream temperature management in both arms. |
| Kim et al.JAMA 2014 · PMID 24240712 · DOI 10.1001/jama.2013.282173 | 1,359 adults resuscitated from prehospital cardiac arrest. | Up to 2 L of 4°C normal saline immediately after ROSC vs standard care. | Core temperature fell ~1.2–1.3°C by hospital arrival and target <34°C was reached about 1 hour earlier. | No improvement in survival or neurological status despite faster cooling. | Large-volume cold fluid is a bundled intervention with fluid load and haemodynamic effects; it is not equivalent to selective respiratory cooling. | METHOD WARNING | Separate thermal effect from delivery burden. Capture fluid balance, haemodynamics, pulmonary status, ventilation and thermal separation. Historical IP context: Fabian Temme is inventor of WO2008017456A1, an infusion system for changing the temperature of infusion fluid, with priority 7 Aug 2006 and publication 14 Feb 2008. This predates the Kim trial enrolment period and publication. No connection, technology transfer or influence between that patent family and the Kim study is asserted or documented here. Patent family reference. |
| PRINCECirculation 2010 · DOI 10.1161/CIRCULATIONAHA.109.931691 | Randomized prehospital cardiac-arrest pilot during CPR. | Intra-arrest transnasal evaporative cooling + standard care vs standard care. | Cooling began during resuscitation rather than after ROSC. | Thermal feasibility demonstrated; not powered for a stable clinical-effect estimate. | Small pilot and different route/device. | FEASIBILITY ARCHETYPE | Use early cohorts to prove deliverability, not efficacy. Measure time-to-start, thermal separation, safety and adherence. |
| PRINCE + PRINCESS pooledCritical Care 2021 · PMID 34103095 | Post-hoc pooled analysis; 851 as-treated, including 325 initial shockable rhythm. | Transnasal intra-arrest cooling vs standard care. | Very early cooling; subgrouped by initial rhythm. | Shockable-rhythm subgroup: favourable discharge outcome 34.2% vs 24.0%; post-hoc/as-treated. | Not a prespecified confirmatory randomized endpoint. | PHENOTYPE GENERATOR | Prospectively enrich, never retrospectively rescue. Define biologically compelling phenotypes before randomisation. |
| ICECAPNCT04217551 · PMID 39044295 | Adult comatose OHCA survivors; 1,158 actual enrolment in current registry record. | Adaptive comparison of cooling duration using closed-loop temperature control. | Duration/dose-finding; 12, 24 and 48 h initial assignments with controlled rewarming. | Weighted 90-day mRS primary endpoint. ClinicalTrials.gov currently shows no posted results. | Answers duration under its own strategy, not whether AIRCHILL works. | DOSE-DESIGN LESSON | Treat duration as a separate dose dimension. Reconstruct onset, depth, rate, duration and rewarming independently. |
| HYPERION + TTM2 IPD meta-analysisPMID 38109117 | 912 unconscious OHCA patients with initial nonshockable rhythm. | 33°C hypothermia vs controlled normothermia. | At least 24 h temperature strategy; harmonised patient-level analysis. | Mortality 80.1% vs 82.1%; unfavourable functional outcome 90.0% vs 89.2%; no significant benefit. | Constrains interpretation of the borderline-positive HYPERION result. | CONSERVATIVE EFFECT PRIOR | Use pooled contemporary evidence to constrain priors. No positive default AIRCHILL effect for nonshockable OHCA without product-specific randomized data. |
| Neonatal transport servo-controlJ Pediatr 2015 · PMID 25684087 · NCT01683383 | 100 newborns with neonatal encephalopathy transported to 9 NICUs. | Servo-regulated cooling device vs usual transport practice. | Target 33–34°C during transfer. | Temperatures in target range: median 73% vs 0%; target reached during transport 80% vs 49%; time to target 44 vs 63 min. | Primarily a temperature-control/transport study, not a neurodevelopmental efficacy trial. | TRANSPORT CONTROL BENCHMARK | Transport precision is measurable. Capture time-in-target, overshoot/undershoot, variability, handover continuity and device autonomy. |
| CoolCotTrials 2025 · PMID 41024221 · ACTRN12623001298606p | Newborns with confirmed/suspected HIE requiring emergency transport. | Battery servo-controlled cooling blanket vs ice-gel packs. | Transport-phase active cooling; target 33–34°C. | Protocol endpoints: target-range temperature on arrival, time to target, time out of range, fluctuation, safety; MRI and 2-year Bayley outcomes planned. | Protocol/ongoing evidence, not efficacy results. | CURRENT TRANSPORT DESIGN | Link process endpoints to later patient outcomes. Use precise thermal transport endpoints now and preserve long-term neurological follow-up. |
Mandatory fields for future records. Study family; citation/DOI/PMID/register ID; population and inclusion phenotype; setting; intervention; comparator; treatment start; temperature target; cooling rate; duration; rewarming; primary endpoint; effect estimate with uncertainty; adverse events; major bias/limitations; evidence status; AIRCHILL transferability grade; specific protocol variable to add/change; health-economic variables worth collecting. Missing information stays explicitly missing rather than being inferred.
Primary verification examples: TTM2 PMID 34133859 / DOI 10.1056/NEJMoa2100591; NICHD HIE PMID 16221780 / DOI 10.1056/NEJMcps050929; POLAR PMID 30357266 / DOI 10.1001/jama.2018.17075; Eurotherm3235 PMID 26444221 / DOI 10.1056/NEJMoa1507581; DeMartini exertional heat-stroke cohort PMID 24983342. This decision register complements, rather than replaces, the full research corpus.
Cold-air inhalation safety · added 23 August 2026
Cold-air evidence is now a dedicated study family.
The cold-air literature is used as a route- and dose-safety evidence family. It does not define a single safe minimum temperature. Temperature, absolute humidity, minute ventilation, peak flow, duration, route and airway susceptibility jointly determine exposure.
| Study / family | Population | Exposure | Finding | Evidence status | Gewonnenes Wissen / AIRCHILL decision |
|---|---|---|---|---|---|
| Marain et al. · 2026 systematic reviewEuropean Respiratory Review · 39 studies · PROSPERO CRD42021290350 | Healthy controls, asthma/EIB and symptomatic populations | Most protocols ~0 to −26 °C; typically 3–10 min, one 30-min exercise protocol | Cold-air challenge was feasible without a major adverse-event pattern; bronchoconstriction and respiratory symptoms are reproducible in susceptible airways. | SOURCED · human synthesis | Known hazard, not unknown toxicity. Bronchospasm/airway resistance, cough, wheeze and dyspnoea become prespecified safety endpoints and stopping rules. |
| Jaeger et al. · 1980PMID 7453516 | 8 healthy adults | Dry air at −40 °C · 10 min · exercise at 80% predicted VO₂max | Upper-esophageal cooling indicated that upper-airway heat-exchange capacity was exceeded; no epithelial/cilia injury endpoint. | TRANSFERRED · extreme short exposure | −40 °C is an exposure precedent, not a safety limit. It cannot justify prolonged endotracheal use. |
| Hartung et al. · 1980PMID 7417121 | 6 healthy adults | −35 °C · 10 min · rest and exercise | No complaints attributable to cold-air inhalation; selected cardiorespiratory variables were not materially affected. | TRANSFERRED · small physiology study | Shows brief extreme-cold tolerance in healthy volunteers; insufficient for tissue safety or critically ill patients. |
| Larsson et al. · 1998 | 8 healthy nonsmokers · crossover | ~−23 °C · ~2 h · intermittent light exercise | Increased inflammatory cells in lower-airway lavage after cold exposure. | SOURCED · mechanistic human | Duration matters. A temperature warmer than the extreme challenge studies can still produce airway inflammation when exposure is long. |
| Eklund et al. · 2022PMID 36053365 | 29 healthy adults | −15 °C · 50 min · rest vs heavy exercise | Small FEV₁ reductions; exercise increased symptoms, CC16 and IL-8 / epithelial-stress signals. | SOURCED · controlled human | Ventilation amplifies dose. Add epithelial-integrity biomarkers and cumulative minute ventilation to AIRCHILL safety work. |
| Clary-Meinesz et al. · 1992PMID 1305479 | Human nasal/tracheal ciliated cells ex vivo | Temperature-dependent ciliary testing | Lower temperature reduced ciliary beat frequency; this is functional inhibition, not proof of immediate cilia destruction at a single inspired-air temperature. | SOURCED · ex vivo | No −32 °C destruction threshold. Direct mucociliary/ciliary recovery remains a clinical data gap. |
| AIRCHILL porcine programmeBMBF Go-Bio 031A530 project evidence | Porcine endotracheal model | ~−20 °C · 6 h | Intact lung histology, stable perfusion/CT and cardiorespiratory observations under tested conditions. | SOURCED project · preclinical | Most route-relevant prolonged evidence. Supports −20 °C as the provisional lower first-generation clinical setpoint, subject to staged human safety validation. |
| Cold-air cardiovascular challengecontrolled human CAD physiology study | Patients with obstructive coronary artery disease | ~−15 °C · 5 min · loose facemask | Cold-air inhalation impaired coronary microvascular response to sympathetic stimulation. | TRANSFERRED · route differs | Add cardiac safety gates. ECG/ischemia, haemodynamics, arrhythmia and vasopressor endpoints belong in early post-arrest AIRCHILL studies. |
Temperature decision record · ASSUMPTION. The present development envelope uses −20 °C as the provisional lowest first-generation clinical setpoint because prolonged product-specific endotracheal preclinical evidence exists there. Human dose escalation should begin warmer (e.g. −10 → −15 → −20 °C) with independent safety review. −25 °C and colder should first re-enter preclinical dose-finding; −30 to −40 °C remain research-only until prolonged route-specific airway, epithelial and mucociliary safety is established. This is a development decision, not a biological injury threshold.
Full 39-study cold-air table and trial watch: Cold-Air Inhalation Safety Evidence →. The uploaded literature review likewise found no defensible −32 °C cilia-destruction threshold and emphasizes temperature × humidity × ventilation × duration rather than temperature alone.
Winter-sport airway evidence · added 24 August 2026
Repeated cold-air hyperventilation adds the cumulative-dose dimension.
Winter athletes are not a direct model of intubated AIRCHILL delivery. They are a valuable natural-exposure model for repeated cold, dry, high-minute-ventilation stress. The strongest new information is therefore about cumulative dose, inflammatory phenotype, epithelial stress and the protective effect of heat/moisture recovery.
| Evidence | Finding | AIRCHILL knowledge gained |
|---|---|---|
| Mäki-Heikkilä et al. 2020Sports Med · systematic review/meta-analysis | 30 studies; physician-diagnosed asthma ~21% and asthma-medication use ~23% among competitive cross-country skiers; biopsy literature also shows airway inflammation in some non-asthmatic skiers. | Cumulative dose must be separated from acute tolerance. Repeat/duration exposure becomes a formal safety dimension. |
| Systematic review 2025PMID 40223161 · 50 studies | Elite cross-country skiers and ice-hockey players show altered immune/inflammatory profiles, commonly neutrophilic or mixed neutrophilic/eosinophilic airway inflammation. | Measure inflammatory phenotype. Do not assume cold-air injury resembles classic eosinophilic allergic asthma. |
| Frischhut et al. 2020−20 °C randomized crossover | HME use attenuated post-exercise FVC/FEV1 changes and respiratory symptoms in winter-sport athletes. | Heat/moisture exchange is mechanistically relevant. Absolute humidity and respiratory water loss belong beside temperature in the exposure record. |
| Eklund et al. 2022 HME−15 °C randomized crossover · PMID 35391634 | HME attenuated FEV1 decline and reduced the plasma CC16 increase from +121% without HME to +27% with HME. | Epithelial stress is modifiable at fixed environmental temperature. This supports temperature × humidity × ventilation rather than a temperature-only safety threshold. |
| −15 °C duration study30 vs 90 min · PMID 35550109 | Overall spirometric effects were limited, while CC16 increased and longer exposure altered leukocyte responses; atopic participants showed greater peripheral-airway/symptom responses. | Susceptibility matters. Asthma/EIB/atopy become exclusion/stratification variables in early human work. |
Protocol decision. Keep −20 °C as a provisional first-generation lower clinical setpoint, but define safety by delivered airway dose: patient-side temperature + absolute humidity + minute ventilation/flow + duration + repetition. Add CC16/epithelial-integrity, bronchoconstriction, symptoms, mucociliary recovery and inflammatory phenotype to the translational safety ladder. Winter-sport prevalence estimates must not be interpreted as AIRCHILL risk estimates because exposure route, duration, population and ventilation are materially different.
Primary verification: PMID 32915429; PMID 40223161; PMID 31755166; PMID 35391634; PMID 35550109. Full evidence family: Cold-Air Inhalation Safety Evidence →.
Double-counting protection
One study can have many records.
TOBY
Primary RCT + school-age follow-up
The follow-up is clinically important, but it is not a second randomized population.
TTM / TTM2
Separate trials, linked secondary analyses
A TTM2 shockable-rhythm secondary analysis is not counted as a new independent RCT.
PRINCE / PRINCESS
Development family
PRINCESS2 pilot participants flow into the main programme; pilot and main trial must not be double-counted as independent efficacy datasets.
ICECAP
Registry + 2026 article
Two records, one adaptive randomized study.
Eurotherm3235
Registry + result article
Same trial family; the adverse functional result remains visible.
COTTIS
Pilot + COTTIS-2
Different development phases should be distinguished but described as one translational programme.
CHILL-ART
Registry + conference result
One RCT; conference data remain preliminary until a full publication is appraised.
AIRCHILL
Report + poster + peer-reviewed subset
Overlapping samples are reported transparently and not simply added together.
Therapeutic-gas decision records
Relevant gas studies translated into AIRCHILL protocol decisions.
The gas programme is treated as a separate intervention axis. A gas can act pharmacologically, alter gas density and heat transfer, change oxygen delivery or introduce its own device hazards. Each candidate is therefore assessed by human evidence level, delivery architecture, timing, safety and the specific engineering or clinical variable it should change.
| Study / gas | Population / model | Exposure | Main finding | Evidence boundary | AIRCHILL decision |
|---|---|---|---|---|---|
| HYBRID II · H₂eClinicalMedicine 2023 · PMID 36969346 | 73 randomized comatose adults after cardiogenic OHCA; multicentre, double-blind trial terminated early during COVID-19. | 2% inhaled H₂ with oxygen for 18 h after ICU admission vs placebo gas; both groups received contemporary post-arrest care including temperature management. | 90-day CPC 1–2: 56% vs 39%, p=0.15. Secondary mRS and survival signals favoured H₂, including 90-day survival 85% vs 61%. | Primary neurological endpoint was not statistically significant and the planned 360-patient trial enrolled only 73. | Highest-priority pharmacological gas for an AIRCHILL factorial programme. First solve ignition/leak/oxygen-enrichment engineering; then separate cooling, H₂ and cooling+H₂ arms. Do not power an AIRCHILL trial from the observed secondary-effect sizes. |
| CPAr · ArgonNCT05482945 · PMID 41079544 | Phase-II multicentre RCT designed for 120 unconscious adult OHCA survivors with an initial shockable rhythm. | 70% Ar / 30% O₂ for 4 h via experimental ventilator vs standard ventilation at 30% O₂. | Primary endpoint is 48-h neuron-specific enolase; secondary endpoints include myocardial injury, MRI, organ function, survival and neurological outcome. | Human efficacy results are not yet established. The programme is translational, based on encouraging preclinical post-arrest work. | High-priority translational benchmark. Argon should be tested as a medicinal-gas adjunct only after AIRCHILL gas delivery is stable. Preserve a biomarker-to-clinical-outcome ladder and avoid treating NSE as a substitute for 90-day neurological benefit. |
| Xenon + hypothermiaJAMA 2016 · 110 randomized patients | Comatose survivors of OHCA. | Closed-system xenon plus 33°C hypothermia for 24 h vs hypothermia alone; mean end-tidal xenon about 48%. | Global white-matter fractional anisotropy was 3.8% higher with xenon, consistent with less MRI-detected white-matter injury. Six-month neurological outcome was not significantly different; mortality difference narrowly missed significance. | The study was powered for an MRI biomarker rather than clinical efficacy. High xenon concentration and closed-loop delivery materially increase system complexity and cost. | Human proof that a gas can add a measurable neurobiological signal on top of cooling. Use xenon primarily as a benchmark for biomarker architecture and combination-study design, not as the first AIRCHILL gas unless recirculation and economics become acceptable. |
| Xenon feasibility / cardiac safetyPMID 23896830 | Post-OHCA patients receiving xenon with therapeutic hypothermia. | Median end-tidal xenon about 47% for roughly 25.5 h. | Feasible without unexpected serious reactions or significant conduction/repolarization abnormalities; exploratory cardiac markers were favourable. | Feasibility/safety evidence does not establish neurological benefit. | Combination safety must be studied explicitly. For every gas, AIRCHILL should prospectively capture arrhythmia, haemodynamics, vasopressor use, pulmonary effects and interaction with temperature management rather than assume gas and cooling risks are independent. |
| Helium-mixed respiratory coolingResuscitation Plus 2025 · PMID 41283153 | Porcine cardiac-arrest / CPR model with direct brain-temperature measurement. | Helium-containing inhaled mixture used for intra-arrest lung cooling; combined protocol also used cold-fluid infusion. | Helium increased brain-cooling efficiency; the combined method lowered brain temperature by about 0.8°C within 10 min while ROSC performance was comparable with conventional resuscitation. | Animal study and bundled intervention; it does not establish a pharmacological helium neuroprotective effect or human clinical benefit. | Top engineering experiment for AIRCHILL. Test helium vs nitrogen-based carrier gas on a bench and then preclinically at matched FiO₂, flow, pressure and inlet temperature. Primary outcomes: heat-transfer coefficient, brain/core cooling rate, airway pressure, gas exchange and sensor accuracy. This is more immediately actionable than a helium drug claim. |
| Inhaled NO · IHCA feasibilityPMID 34229057 | 20 adults after in-hospital cardiac arrest compared with 199 registry controls. | iNO added after ROSC to standard post-resuscitation care. | Feasible; unmatched survival to discharge was higher, but favourable neurological outcome was not significantly different. | Small non-randomized feasibility study with historical/registry controls; cannot establish efficacy. | Keep as a secondary research candidate. Any AIRCHILL+iNO study needs randomized confirmation and patient-near NO/NO₂/FiO₂ monitoring, methemoglobin surveillance and clear separation of pulmonary-haemodynamic effects from neuroprotection. |
| iNO during/after CPR · preclinicalPMID 26369409 · PMID 26577797 | Porcine and rat cardiac-arrest models. | Typically 20 ppm iNO started during CPR and continued into early post-ROSC care. | Reported improvements in perfusion, biomarkers, neurological performance and survival in animal models. | Preclinical dose-response and species effects cannot be transferred directly to human efficacy or to AIRCHILL. | Timing is part of the gas dose. If iNO is revisited, compare intra-arrest vs post-ROSC start rather than treating “iNO exposure” as one intervention. |
Gas-programme priority after this review. 1) H₂ for the strongest directly randomized human clinical signal at a low inspired concentration; 2) helium for AIRCHILL-specific heat-transfer engineering; 3) argon as the strongest active translational noble-gas programme; 4) xenon as the best human biomarker precedent but with substantial closed-loop/cost complexity; 5) inhaled NO as a monitored secondary candidate. CO, N₂O and H₂S stay outside the near-term clinical programme unless materially stronger human safety/efficacy evidence appears.
Open the helium carrier-gas study protocol →
Open the helium carrier-gas study protocol →
Safety and hidden treatment dose
The cooling device is only part of the intervention.
Arrhythmia, circulation, coagulation, infection, electrolytes, drug handling, shivering, sedation and rewarming can all move the benefit–risk balance. Selective systems add route-specific risks.
Heart / circulation
Rhythm and haemodynamics
Deeper cooling can increase bradycardia, arrhythmia burden and the need for haemodynamic support.
Coagulation
Bleeding must be a prespecified safety endpoint
Especially relevant in trauma, intracranial bleeding, thrombectomy and anticoagulated patients.
Infection
Fever suppression can hide a signal
Cooling can alter immune response; pneumonia recurs as a concern in several evidence families.
Metabolism
Electrolytes, glucose and drug clearance change
Rewarming can reverse shifts that developed during cooling, making the end phase part of the dose.
Treatment burden
Shivering changes the protocol
Analgesia, sedation and neuromuscular blockade can affect blood pressure, neurological examination and ventilation.
AIRCHILL-specific
Airway and gas-path safety
Mucosa, secretion handling, condensation, resistance, pressure, gas exchange and lung tissue need dedicated testing.
Editorial & agent framing rule. Development-stage goals are written positively and prospectively: lead with the observed mechanism, preclinical evidence and the clinical question the next study is designed to test and size. State the evidence boundary in the same paragraph, but do not headline an unresolved objective as failure (for example, “not shown”, “no evidence” or “not promising”) when the accurate meaning is “next validation target”. Neutral and negative studies remain visible and are used to improve route, timing, phenotype, dose, safety and endpoint design. Preclinical or subgroup signals are never presented as established human efficacy. English-source rule: substantive evidence and claim-framing changes are authored in English first; translations follow the versioned English source.
The 33,808-record corpus
The large table is a screening instrument, not a scoreboard.
The uploaded research register contains journal records, reviews, case reports, randomized trials, registry records, observational studies and guidelines. It is intentionally broader than the set that can support website claims. The on-site evidence map and trial table therefore expose the manually appraised decision points rather than forcing a visitor to load more than 20 MB of raw metadata.
23,777journal records
1,400records typed as randomized controlled trials
1,334clinical-trial registry records across the combined source register
503systematic reviews / meta-analyses
83guidelines
Screening rule. Only records marked included in the curated evidence workflow may carry result claims. Candidate records remain searchable research leads, not evidence statements. Negative and neutral studies are retained, and publication families are linked to prevent double counting.
The full raw research register remains a versioned research appendix. Because it contains 33,808 metadata rows, possible false positives and repeated study families, it is deliberately not injected into every public page load. The public table above is the claim-relevant navigation layer.
What this means for AIRCHILL.
The development thesis is specific and testable: AIRCHILL has already demonstrated rapid local brain-temperature change, preclinical airway tolerance and a fast onset of effect; external animal work shows that timing, depth and duration can materially influence neuroprotection. The next programme is designed to reproduce and strengthen product-level thermal performance, establish patient safety and test whether this very early controlled exposure improves patient-relevant outcomes in selected indications. Those clinical objectives remain to be established prospectively, and this research map defines the studies required to measure them.
Open the clinical study plannerOpen global impact modelsSources & assumptions
Research disclosure. Medical Cooling is an interested party in AIRCHILL. Project documents are used as primary sources for what was built and measured, not as independent proof of clinical efficacy. External trials are not product validation.
Platform evidence rule. Mature functions such as ECG/monitoring, defibrillation, suction and connectivity may be integrated through qualified purchased or OEM technology rather than re-developed as AIRCHILL inventions. Evidence or regulatory status of an OEM module does not automatically validate the integrated AIRCHILL system: supplier qualification, interfaces, alarms, EMC/electrical interactions, software/data dependencies, cybersecurity, usability and system-level essential performance remain part of the AIRCHILL evidence package.
Platform evidence rule. Mature functions such as ECG/monitoring, defibrillation, suction and connectivity may be integrated through qualified purchased or OEM technology rather than re-developed as AIRCHILL inventions. Evidence or regulatory status of an OEM module does not automatically validate the integrated AIRCHILL system: supplier qualification, interfaces, alarms, EMC/electrical interactions, software/data dependencies, cybersecurity, usability and system-level essential performance remain part of the AIRCHILL evidence package.