Dear Editor,
Survivorship after cardiac arrest (CA) has increasingly become a central focus of post-resuscitation care. Many survivors experience difficulties across multiple, interrelated domains of recovery, which are not easily captured by global functional scales such as the Cerebral Performance Category,1, 2, 3 and recent initiatives reflect this shift, moving beyond static neurological categories to examine longitudinal recovery trajectories, patient-reported outcomes, and multidomain support strategies.3, 4 The ENFORCER trial (NCT06395558) evaluates an internet-based educational intervention targeting anxiety, depression, and cognitive impairment in CA survivors identified through early post-discharge screening, with initial contact within two weeks.5
After one year of enrolment, a blinded, descriptive interim feasibility analysis—non-comparative and focused on recruitment trends, data completeness, and stability of symptom trajectories—was conducted: of 115 eligible survivors, 96 were contacted, 51 consented to screening, and 27 were randomized based on cognitive or emotional symptoms. This analysis revealed marked fluctuations in cognitive and especially emotional symptoms during the first year after CA. Fig. 1 illustrates the anxiety, depression, cognitive impairment, and quality-of-life trajectories for the 33 survivors enrolled and randomized as of March 23, 2026. Notably, four survivors showed early improvement followed by later worsening, while seven developed new symptoms in previously unaffected domains.
Fig. 1.
Individual and mean trajectories of anxiety, depression, quality of life, and cognitive function over 48 weeks in 33 OHCA survivors enrolled and randomized as of March 23, 2026.
Notes: Thin lines represent individual participant trajectories; bold lines represent group means. The dashed line denotes the mean trajectory; the gray band represents the standard error of the mean for the collected sample.
Abbreviations: HADS-A – Hospital Anxiety and Depression Scale, Anxiety subscale; HADS-D – Hospital Anxiety and Depression Scale, Depression subscale; MCS-12 – Mental Component Summary of the SF-12; PCS-12 – Physical Component Summary of the SF-12; TICS – Telephone Interview for Cognitive Status.
These early divergences and non-linear patterns suggest that relying on a single early symptom screen for enrolment may limit the ability to identify survivors who could benefit from educational interventions. This has implications for defining eligibility criteria, determining the timing of enrolment, and selecting outcomes, because early thresholds may fail to capture survivors whose emotional, cognitive, or quality-of-life impairments emerge later. Prior CA research supports this interpretation: a longitudinal study showed group-level improvements in emotional outcomes while a substantial subgroup worsened,6 and a contemporary multicentre investigation confirmed persistent interindividual variability beyond six months.7 Qualitative studies further describe fluctuating recovery, delayed psychological burden, and the emergence of new symptoms after an initial period of stability.8
In light of these considerations, the ENFORCER steering committee implemented a protocol amendment, in which eligibility criteria were expanded to include all OHCA survivors regardless of baseline HADS or TICS scores, and health-related quality of life (Short Form Heath Survey – SF-12) was elevated from a secondary to the primary outcome. This aligns the endpoint with the trial’s emphasis on preventive and supportive care, particularly given the inclusion of survivors without baseline emotional or cognitive symptoms. The sample size was recalculated to detect a minimal clinically relevant difference of 4 points in SF-12, the best available estimate for a chronic disease population,9 and the recruitment period was extended. The amendment was approved by the Ethics Committee, implemented in February 2026, and prospectively updated in the trial registry. More broadly, our experience supports the evidence that recovery after CA is a time-varying, multidomain process. Supportive trials must therefore consider eligibility, timing, and outcome selection in ways that reflect this complexity, as early symptom thresholds alone may fail to identify survivors whose needs emerge later.10
CRediT authorship contribution statement
Lorenzo Gamberini: Writing – original draft, Conceptualization. Martina Masi: Writing – review & editing, Conceptualization. Daniele Celin: Investigation. Riccardo Tucci: Investigation. Elio Fabbri: Visualization.
Funding
This study is funded by a research grant from Fondazione Italian Resuscitation Council (https://www.fondazioneirc.org/), a not-for-profit organization involved in the assistance and support for cardiac arrest survivors and their families. Fondazione IRC has had only a financial role and has no control over data, results publication and intellectual property of eventual results.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributor Information
Lorenzo Gamberini, Email: lorenzo.gamberini@ausl.bologna.it.
ENFORCER Network:
Carlo Coniglio, Giovanni Giuliani, Jonathan Montomoli, Chiara Capozzi, Mattia Garofalo, Gianluca Zani, Concetta Lanza, Savino Spadaro, Milo Vason, Maila Mancini, Tommaso Tonetti, Gabriele Melegari, Carlo Pegani, Michele Zuliani, Alice Pravisani, Davide Colombo, Giammaria Cammarota, Rosanna Vaschetto, Giuseppe Ristagno, Nicola Pedroni, Emanuele Rezoagli, Giuseppe Marchese, Giovanni Mistraletti, Fabio Sangalli, Martina Locatelli, Cristina Panzeri, Francesca Zanon, Giulia Roveri, Vittorio Pavoni, Giuliano Michelagnoli, Iacopo Cappellini, Federica Stella, Sonia D’Arrigo, Filippo Sanfilippo, Paolo Murabito, Mariachiara Ippolito, Luca Carenzo, Annalisa Piccolo, Marianna Madia, Cristina Santonocito, Jessica Giuseppina Maugeri, Carola Matellon, Matteo Filippini, Riccardo Tucci, Daniele Celin, Guglielmo Imbriaco, Pamela Salucci, Paola Rucci, Camilla Dolcini, Laura Simoncini, Donatella Del Giudice, Rosa Domina, Andrea Fagiolini, and Marco Tartaglione
Appendix 1.
ENFORCER Network
| Collaborator details | Affiliation |
|---|---|
| Carlo Coniglio | Maggiore Hospital – Bologna, Italy |
| Giovanni Giuliani | Infermi Hospital – Rimini, Italy |
| Jonathan Montomoli | Infermi Hospital, Department of Anesthesia and Intensive Care, Rimini, Italy |
| Chiara Capozzi | Cardio-Thoracic and Vascular Anesthesia and Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy |
| Mattia Garofalo | Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum Università di Bologna, Italy |
| Gianluca Zani | Lugo Hospital – Lugo, Italy |
| Concetta Lanza | Morgagni-Pierantoni Hospital – Forlì, Italy |
| Savino Spadaro | Sant’Anna Hospital – University Intensive Care Unit – Ferrara, Italy |
| Milo Vason | Sant’Anna Hospital – Hospital Intensive Care Unit – Ferrara, Italy |
| Maila Mancini | Santa Maria delle Croci Hospital – Ravenna – Anesthesia and Intensive Care – Ravenna, Italy |
| Tommaso Tonetti | Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna – Bologna, Italy |
| Anesthesiology and General Intensive Care Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna – Bologna, Italy | |
| Gabriele Melegari | Sant'Agostino Estense Hospital – Baggiovara, Italy |
| Carlo Pegani | ASUGI, Healthcare University Unit Giuliano Isontina – Trieste, Italy |
| Michele Zuliani | ASUFC – Santissima Maria della Misericordia Hospital – Udine, Italy |
| Alice Pravisani | ASFO – Santa Maria degli angeli di Pordenone Hospital, Italy |
| Davide Colombo | Ss. Trinità Hospital – Borgomanero, Italy |
| Giammaria Cammarota | Department of Traslational Medicine, Università degli Studi del Piemonte Orientale – Novara, Italy |
| Department of Anesthesiology and General Intensive Care, AOUAL – Azienda Ospedaliero Universitaria “SS Antonio e Biagio e Cesare Arrigo” – Alessandria, Italy | |
| SIMNOVA Simulation Center – Università degli Studi del Piemonte Orientale, Novara – Alessandria, Italy | |
| Rosanna Vaschetto | Department of Traslational Medicine, Università degli Studi del Piemonte Orientale – Novara, Italy |
| Giuseppe Ristagno | Department of Pathophysiology and Transplantation, University of Milan – Milan, Italy |
| Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico – Milan, Italy | |
| Nicola Pedroni | Anesthesia and General and Neurosurgical Intensive Care. Di Circolo Hospital – Varese, Italy |
| Emanuele Rezoagli | General Intensive Care, San Gerardo dei Tintori Hospital – Monza, Italy |
| Giuseppe Marchese | Anesthesia and Intensive Care, Legnano Hospital – Legnano, Italy |
| Giovanni Mistraletti | University of Milan, Milan, Italy |
| Anesthesia and Intensive Care, Legnano Hospital – Legnano, Italy | |
| Fabio Sangalli | Anesthesia and Intensive Care, ASST Valtellina e Alto Lario, Sondrio, Italy |
| Martina Locatelli | Anesthesia and Intensive Care, ASST Valtellina e Alto Lario, Sondrio, Italy |
| Cristina Panzeri | Anesthesia and Intensive Care, Manzoni Hospital- Lecco, Italy |
| Francesca Zanon | Department of Anesthesia and Critical Care 1, S. Chiara Hospital, ASUIT Trento, Trento, Italy |
| Giulia Roveri | Department of Anesthesia and Intensive Care Medicine, “F. Tappeiner” Hospital Merano, Merano, Italy |
| Vittorio Pavoni | Santa Maria Annunziata Hospital, Toscana Centro Healthcare Agency – Bagno a Ripoli, Italy |
| Giuliano Michelagnoli | San Jacopo Hospital – Pistoia, Italy |
| Iacopo Cappellini | Santo Stefano Hospital – Prato, Italy |
| Federica Stella | 118 Dispatch Center – Venice, Italy |
| Sonia D'Arrigo | Department of Anesthesiology Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS – Rome, Italy |
| Filippo Sanfilippo | G Rodolico – San Marco University Hospital – Anesthesia and Intensive Care 1 – Catania, Italy |
| Paolo Murabito | G Rodolico – San Marco University Hospital – Anesthesia and Intensive Care 2 – Catania, Italy |
| Mariachiara Ippolito | Anesthesia and Intensive Care, Paolo Giaccone University Hospital – Palermo, Italy |
| Luca Carenzo | Anesthesia and Intensive Care, IRCCS Humanitas Research Hospital – Milano, Italy |
| Annalisa Piccolo | Anesthesia and Intensive Care, Metropolitan Hospital Bianchi Melacrino Morelli – Reggio Calabria, Italy |
| Marianna Madia | Anesthesia and Intensive Care, V. Fazzi Hospital – Lecce, Italy |
| Cristina Santonocito | Anesthesia and Intensive Care, Policlinico Sano Marco – Catania, Italy |
| Jessica Giuseppina Maugeri | Anesthesia and Intensive Care, Garibaldi Centro Hospital, ANAS Garibaldi – Catania, Italy |
| Carola Matellon | Division of Cardio-Thoracic Intensive Care, ASST Spedali Civili – Brescia, Italy |
| Matteo Filippini | Department of Anesthesia, Intensive Care and Emergency, ASST Spedali Civili University Hospital – Brescia, Italy |
| Riccardo Tucci | Department of Anesthesia, Intensive Care and Prehospital Emergency, Maggiore Hospital Carlo Alberto Pizzardi, Bologna, Italy. |
| Daniele Celin | 118 Emilia Est, Prehospital Emergency Dispatch Center, Helicopter Emergency Medical Service, Maggiore Hospital Carlo Alberto Pizzardi, Bologna, Italy |
| Guglielmo Imbriaco | 118 Emilia Est, Prehospital Emergency Dispatch Center, Helicopter Emergency Medical Service, Maggiore Hospital Carlo Alberto Pizzardi, Bologna, Italy |
| Pamela Salucci | Neurorehabilitation Unit for Severe Cerebrolesions, Montecatone Rehabilitation Institute, Imola, Italy |
| Paola Rucci | Department of Biomedical and Neuromotor Sciences – University of Bologna, Bologna, Italy |
| Camilla Dolcini | Neurorehabilitation Unit for Severe Cerebrolesions, Montecatone Rehabilitation Institute, Imola, Italy |
| Laura Simoncini | Spinal Unit, Montecatone Rehabilitation Institute, Imola, Italy |
| Donatella Del Giudice | Regional Program prehospital Emergency 118 – Maggiore Hospital, Bologna, Italy |
| Rosa Domina | Data Protection Office, Bologna Local Health Authority, Bologna, Italy |
| Andrea Fagiolini | Integrated Department of Mental Health and Sensory Organs – University of Siena, Siena, Italy |
| Marco Tartaglione | Department of Intensive Care and Prehospital Emergency, Emergency Department, Maggiore Hospital, Bologna, Italy |
References
- 1.Nolan J.P., Sandroni C., Cariou A., Cronberg T., D’Arrigo S., Haywood K., et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2025 post-resuscitation care. Resuscitation. 2025;215 doi: 10.1016/j.resuscitation.2025.110809. [DOI] [PubMed] [Google Scholar]
- 2.Dainty K.N., Wagner A.K., Wood M., Agarwal S. Wolf Creek XVIII Part 5: cardiac arrest survivorship science. Resusc Plus. 2026;28 doi: 10.1016/j.resplu.2026.101266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Douma M.J., Myhre C., Ali S., Graham T.A.D., Ruether K., Brindley P.G., et al. What are the care needs of families experiencing sudden cardiac arrest? A survivor- and family-performed systematic review, qualitative meta-synthesis, and clinical practice recommendations. J Emerg Nurs. 2023;49:912–950. doi: 10.1016/j.jen.2023.07.001. [DOI] [PubMed] [Google Scholar]
- 4.Agarwal S., Wagner M.K., Mion M. Psychological and behavioral dimensions in cardiac arrest survivors and their families: a state-of-the-art review. Neurotherapeutics. 2025;22 doi: 10.1016/j.neurot.2024.e00509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Gamberini L., Rucci P., Dolcini C., Masi M., Simoncini L., Tartaglione M., et al. ENFORCER, internet-based interventions for cardiac arrest survivors: a study protocol for a randomised, parallel-group, multicentre clinical trial. Resusc Plus. 2024;20 doi: 10.1016/j.resplu.2024.100772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Viktorisson A., Sunnerhagen K.S., Johansson D., Herlitz J., Axelsson Å. One-year longitudinal study of psychological distress and self-assessed health in survivors of out-of-hospital cardiac arrest. BMJ Open. 2019;9 doi: 10.1136/bmjopen-2019-029756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hultgren M., Blennow Nordström E., Ullén S., Nielsen N., Dankiewicz J., Jakobsen J.C., et al. Long-term outcomes and recovery trajectories in out-of-hospital cardiac arrest: a 2-year follow-up of the randomized clinical TTM2 trial. JAMA Neurol. 2026 doi: 10.1001/jamaneurol.2025.5614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Southern C., Tutton E., Dainty K.N., Seers K., Pearson N.A., Couper K., et al. The experiences of cardiac arrest survivors and their key supporters following cardiac arrest: a systematic review and meta-ethnography. Resuscitation. 2024;198 doi: 10.1016/j.resuscitation.2024.110188. [DOI] [PubMed] [Google Scholar]
- 9.Díaz-Arribas M.J., Fernández-Serrano M., Royuela A., Kovacs F.M., Gallego-Izquierdo T., Ramos-Sánchez M., et al. Minimal clinically important difference in quality of life for patients with low back pain. Spine (Phila Pa) 1976;2017(42):1908–1916. doi: 10.1097/BRS.0000000000002298. [DOI] [PubMed] [Google Scholar]
- 10.Mion M., Presciutti A. Trials that can scale: five pillars for cardiac arrest survivorship research. Resuscitation. 2026;222 doi: 10.1016/j.resuscitation.2026.111075. [DOI] [PubMed] [Google Scholar]