BACKGROUND: Randomized trials have shown that trans-nasal evaporative cooling initiated during CPR (i.e. intra-arrest) effectively lower core body temperature in out-of-hospital cardiac arrest patients. However, these trials may have been underpowered to detect significant differences in neurologic outcome, especially in patients with initial shockable rhythm. METHODS: We conducted a post hoc pooled analysis of individual data from two randomized trials including 851 patients who eventually received the allocated intervention and with available outcome ("as-treated" analysis). Primary outcome was survival with favourable neurological outcome at hospital discharge (Cerebral Performance Category [CPC] of 1-2) according to the initial rhythm (shockable vs. non-shockable). Secondary outcomes included complete neurological recovery (CPC 1) at hospital discharge. RESULTS: Among the 325 patients with initial shockable rhythms, favourable neurological outcome was observed in 54/158 (34.2%) patients in the intervention and 40/167 (24.0%) in the control group (RR 1.43 [confidence intervals, CIs 1.01-2.02]). Complete neurological recovery was observed in 40/158 (25.3%) in the intervention and 27/167 (16.2%) in the control group (RR 1.57 [CIs 1.01-2.42]). Among the 526 patients with initial non-shockable rhythms, favourable neurological outcome was in 10/259 (3.8%) in the intervention and 13/267 (4.9%) in the control group (RR 0.88 [CIs 0.52-1.29]; p = 0.67); survival and complete neurological recovery were also similar between groups. No significant benefit was observed for the intervention in the entire population. CONCLUSIONS: In this pooled analysis of individual data, intra-arrest cooling was associated with a significant increase in favourable neurological outcome in out-of-hospital cardiac arrest patients with initial shockable rhythms. Future studies are needed to confirm the potential benefits of this intervention in this subgroup of patients.
BACKGROUND: To date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear. METHODS/DESIGN: The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33 °C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (≥ 37.8 °C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180 days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4-6) at 180 days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan. DISCUSSION: This SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.
- MeSH
- horečka MeSH
- hypotermie * MeSH
- kardiopulmonální resuscitace * MeSH
- lidé MeSH
- tělesná teplota MeSH
- terapeutická hypotermie * škodlivé účinky MeSH
- výsledek terapie MeSH
- zástava srdce mimo nemocnici * diagnóza terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
PURPOSE: To study the association between early initiation of intra-arrest therapeutic hypothermia and neurologic outcome in out-of-hospital cardiac arrest. METHODS: A prespecified sub-analysis of the PRINCESS trial (NCT01400373) that randomized 677 bystander-witnessed cardiac arrests to transnasal evaporative intra-arrest cooling initiated by emergency medical services or cooling started after hospital arrival. Early cooling (intervention) was defined as intra-arrest cooling initiated < 20 min from collapse (i.e., ≤ median time to cooling in PRINCESS). Propensity score matching established comparable control patients. Primary outcome was favorable neurologic outcome, Cerebral Performance Category (CPC) 1-2 at 90 days. Complete recovery (CPC 1) was among secondary outcomes. RESULTS: In total, 300 patients were analyzed and the proportion with CPC 1-2 at 90 days was 35/150 (23.3%) in the intervention group versus 24/150 (16%) in the control group, odds ratio (OR) 1.92, 95% confidence interval (CI) 0.95-3.85, p = .07. In patients with shockable rhythm, CPC 1-2 was 29/57 (50.9%) versus 17/57 (29.8%), OR 3.25, 95%, CI 1.06-9.97, p = .04. The proportion with CPC 1 at 90 days was 31/150 (20.7%) in the intervention group and 17/150 (11.3%) in controls, OR 2.27, 95% CI 1.12-4.62, p = .02. In patients with shockable rhythms, the proportion with CPC 1 was 27/57 (47.4%) versus 12/57 (21.1%), OR 5.33, 95% CI 1.55-18.3, p = .008. CONCLUSIONS: In the whole study population, intra-arrest cooling initiated < 20 min from collapse compared to cooling initiated at hospital was not associated with improved favorable neurologic outcome. In the subgroup with shockable rhythms, early cooling was associated with improved favorable outcome and complete recovery.
AIMS: The TTM2-trial is a multi-centre randomised clinical trial where targeted temperature management (TTM) at 33 °C will be compared with normothermia and early treatment of fever (≥37.8 °C) after Out-of-Hospital Cardiac Arrest (OHCA). This paper presents the design and rationale of the TTM2-trial follow-up, where information on secondary and exploratory outcomes will be collected. We also present the explorative outcome analyses which will focus on neurocognitive function and societal participation in OHCA-survivors. METHODS: Blinded outcome-assessors will perform follow-up at 30-days after the OHCA with a telephone interview, including the modified Rankin Scale (mRS) and the Glasgow Outcome Scale Extended (GOSE). Face-to-face meetings will be performed at 6 and 24-months, and include reports on outcome from several sources of information: clinician-reported: mRS, GOSE; patient-reported: EuroQol-5 Dimensions-5 Level responses version (EQ-5D-5L), Life satisfaction, Two Simple Questions; observer-reported: Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest version (IQCODE-CA) and neurocognitive performance measures: Montreal Cognitive Assessment, (MoCA), Symbol Digit Modalities Test (SDMT). Exploratory analyses will be performed with an emphasis on brain injury in the survivors, where the two intervention groups will be compared for potential differences in neuro-cognitive function (MoCA, SDMT) and societal participation (GOSE). Strategies to increase inter-rater reliability and decrease missing data are described. DISCUSSION: The TTM2-trial follow-up is a pragmatic yet detailed pre-planned and standardised assessment of patient's outcome designed to ensure data-quality, decrease missing data and provide optimal conditions to investigate clinically relevant effects of TTM, including OHCA-survivors' neurocognitive function and societal participation.
- MeSH
- hypotermie * MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- následné studie MeSH
- randomizované kontrolované studie jako téma MeSH
- reprodukovatelnost výsledků MeSH
- senioři MeSH
- terapeutická hypotermie * MeSH
- výsledek terapie MeSH
- zástava srdce mimo nemocnici * terapie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- protokol klinické studie MeSH
Importance: Therapeutic hypothermia may increase survival with good neurologic outcome after cardiac arrest. Trans-nasal evaporative cooling is a method used to induce cooling, primarily of the brain, during cardiopulmonary resuscitation (ie, intra-arrest). Objective: To determine whether prehospital trans-nasal evaporative intra-arrest cooling improves survival with good neurologic outcome compared with cooling initiated after hospital arrival. Design, Setting, and Participants: The PRINCESS trial was an investigator-initiated, randomized, clinical, international multicenter study with blinded assessment of the outcome, performed by emergency medical services in 7 European countries from July 2010 to January 2018, with final follow-up on April 29, 2018. In total, 677 patients with bystander-witnessed out-of-hospital cardiac arrest were enrolled. Interventions: Patients were randomly assigned to receive trans-nasal evaporative intra-arrest cooling (n = 343) or standard care (n = 334). Patients admitted to the hospital in both groups received systemic therapeutic hypothermia at 32°C to 34°C for 24 hours. Main Outcomes and Measures: The primary outcome was survival with good neurologic outcome, defined as Cerebral Performance Category (CPC) 1-2, at 90 days. Secondary outcomes were survival at 90 days and time to reach core body temperature less than 34°C. Results: Among the 677 randomized patients (median age, 65 years; 172 [25%] women), 671 completed the trial. Median time to core temperature less than 34°C was 105 minutes in the intervention group vs 182 minutes in the control group (P < .001). The number of patients with CPC 1-2 at 90 days was 56 of 337 (16.6%) in the intervention cooling group vs 45 of 334 (13.5%) in the control group (difference, 3.1% [95% CI, -2.3% to 8.5%]; relative risk [RR], 1.23 [95% CI, 0.86-1.72]; P = .25). In the intervention group, 60 of 337 patients (17.8%) were alive at 90 days vs 52 of 334 (15.6%) in the control group (difference, 2.2% [95% CI, -3.4% to 7.9%]; RR, 1.14 [95% CI, 0.81-1.57]; P = .44). Minor nosebleed was the most common device-related adverse event, reported in 45 of 337 patients (13%) in the intervention group. The adverse event rate within 7 days was similar between groups. Conclusions and Relevance: Among patients with out-of-hospital cardiac arrest, trans-nasal evaporative intra-arrest cooling compared with usual care did not result in a statistically significant improvement in survival with good neurologic outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT01400373.
- MeSH
- čas zasáhnout při rozvinutí nemoci MeSH
- epistaxe etiologie MeSH
- jednoduchá slepá metoda MeSH
- kardiopulmonální resuscitace metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- mozek patofyziologie MeSH
- poranění mozku etiologie prevence a kontrola MeSH
- senioři MeSH
- terapeutická hypotermie škodlivé účinky přístrojové vybavení metody MeSH
- urgentní zdravotnické služby * MeSH
- velikost vzorku MeSH
- výsledek terapie MeSH
- zástava srdce mimo nemocnici komplikace mortalita terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
