{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T21:24:49Z","timestamp":1789680289875,"version":"4.0.1"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:00:00Z","timestamp":1716940800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:00:00Z","timestamp":1716940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001922","name":"Efficacy and Mechanism Evaluation Programme","doi-asserted-by":"publisher","award":["NIHR129875"],"award-info":[{"award-number":["NIHR129875"]}],"id":[{"id":"10.13039\/501100001922","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Paediatric convulsive status epilepticus is the most common neurological emergency presenting to emergency departments. Risks of resultant neurological morbidity and mortality increase with seizure duration. If the seizure fails to stop within defined time-windows, standard care follows an algorithm of stepwise escalation to more intensive treatments, ultimately resorting to induction of general anaesthesia and ventilation. Additionally, ventilatory support may also be required to treat respiratory depression, a common unwanted effect of treatment. There is strong pre-clinical evidence that pH (acid\u2013base balance) is an important determinant of seizure commencement and cessation, with seizures tending to start under alkaline conditions and terminate under acidic conditions. These mechanisms may be particularly important in febrile status epilepticus: prolonged fever-related seizures which predominantly affect very young children. This trial will assess whether imposition of mild respiratory acidosis by manipulation of inhaled medical gas improves response rates to first-line medical treatment.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A double-blind, placebo-controlled trial of pH manipulation as an adjunct to standard medical treatment of convulsive status epilepticus in children. The control arm receives standard medical management whilst inhaling 100% oxygen; the active arm receives standard medical management whilst inhaling a commercially available mixture of 95% oxygen, 5% carbon dioxide known as \u2018carbogen\u2019.<\/jats:p>\n                <jats:p>Due to the urgent need to treat the seizure, deferred consent is used.\n<\/jats:p>\n                <jats:p>The primary outcome is success of first-line treatment in seizure cessation. Planned subgroup analyses will be undertaken for febrile and non-febrile seizures. Secondary outcomes include rates of induction of general anaesthesia, admission to intensive care, adverse events, and 30-day mortality.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>If safe and effective 95% oxygen, 5% carbon dioxide may be an important adjunct in the management of convulsive status epilepticus with potential for pre-hospital use by paramedics, families, and school staff.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>EudraCT: 2021-005367-49. CTA: 17136\/0300\/001. ISRCTN: 52731862. Registered on July 2022.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-024-08188-5","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T06:03:22Z","timestamp":1716962602000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Seizure control via pH manipulation: a phase II double-blind randomised controlled trial of inhaled carbogen as adjunctive treatment of paediatric convulsive status epilepticus (Carbogen for Status Epilepticus in Children Trial (CRESCENT))"],"prefix":"10.1186","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-4180","authenticated-orcid":false,"given":"Rob","family":"Forsyth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Bedson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Downes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Gough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Hartshorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Lawton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D.","family":"Lyttle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrouk","family":"Messahel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niall","family":"Mullen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Raper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rosala-Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh","family":"Taggart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Urron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Walton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrol","family":"Gamble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the Paediatric Emergency Research in the United Kingdom and Ireland (PERUKI) collaborative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriel","family":"Tolhurst-Cleaver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Siner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandi","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Ledger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Amos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice J.","family":"Downes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Mikhail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor","family":"Alhashimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"key":"8188_CR1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/S0140-6736(06)69043-0","volume":"368","author":"RFM Chin","year":"2006","unstructured":"Chin RFM, Neville BGR, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet. 2006;368:222\u20139.","journal-title":"Lancet"},{"key":"8188_CR2","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.seizure.2019.06.008","volume":"71","author":"A Higgins","year":"2019","unstructured":"Higgins A, Downes C, Varley J, Doherty CP, Begley C, Elliott N. Supporting and empowering people with epilepsy: Contribution of the Epilepsy Specialist Nurses (SENsE study). Seizure. 2019;71:42\u20139.","journal-title":"Seizure"},{"key":"8188_CR3","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/S1474-4422(08)70141-8","volume":"7","author":"RF Chin","year":"2008","unstructured":"Chin RF, Neville BG, Peckham C, Wade A, Bedford H, Scott RC. Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol. 2008;7:696\u2013703.","journal-title":"Lancet Neurol"},{"key":"8188_CR4","volume-title":"Advanced Paediatric Life Support","author":"Advanced Life Support Group","year":"2016","unstructured":"Advanced Life Support Group. Advanced Paediatric Life Support. Chichester: Wiley; 2016."},{"key":"8188_CR5","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1111\/j.1528-1167.2007.01297.x","volume":"48","author":"HP Goodkin","year":"2007","unstructured":"Goodkin HP, Sun C, Yeh J-L, Mangan PS, Kapur J. GABA-A receptor internalization during seizures. Epilepsia. 2007;48:109\u201313.","journal-title":"Epilepsia"},{"key":"8188_CR6","doi-asserted-by":"publisher","first-page":"3482","DOI":"10.1093\/brain\/awz283","volume":"142","author":"RJ Burman","year":"2019","unstructured":"Burman RJ, Selfe JS, Lee JH, et al. Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus. Brain. 2019;142:3482\u2013501.","journal-title":"Brain"},{"key":"8188_CR7","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1136\/jnnp.2003.032797","volume":"75","author":"RFM Chin","year":"2004","unstructured":"Chin RFM, Verhulst L, Neville BGR, Peters MJ, Scott RC. Inappropriate emergency management of status epilepticus in children contributes to need for intensive care. J Neurol Neurosurg Psychiatry. 2004;75:1584\u20138.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"8188_CR8","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1016\/S0140-6736(19)30724-X","volume":"393","author":"MD Lyttle","year":"2019","unstructured":"Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet. 2019;393:2125\u201334.","journal-title":"Lancet"},{"key":"8188_CR9","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1111\/j.1528-1167.2010.02731.x","volume":"52","author":"EA Tolner","year":"2011","unstructured":"Tolner EA, Hochman DW, Ot\u00e1hal J, et al. Five percent CO2 is a potent, fast-acting inhalation anticonvulsant. Epilepsia. 2011;52:104\u201314.","journal-title":"Epilepsia"},{"key":"8188_CR10","first-page":"1","volume-title":"Carbonic anhydrases and brain pH in the control of neuronal excitability","author":"E Ruusuvuori","year":"2014","unstructured":"Ruusuvuori E, Kaila K. Carbonic anhydrases and brain pH in the control of neuronal excitability. Dordrecht: Springer Netherlands; 2014. p. 1."},{"key":"8188_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/cs0790001","volume":"79","author":"TA Cadoux-Hudson","year":"1990","unstructured":"Cadoux-Hudson TA, Rajagopalan B, Ledingham JG, Radda GK. Response of the human brain to a hypercapnic acid load in vivo. Clin Sci (Lond). 1990;79:1\u20133.","journal-title":"Clin Sci (Lond)"},{"key":"8188_CR12","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1152\/physrev.00010.2003","volume":"83","author":"M Chesler","year":"2003","unstructured":"Chesler M. Regulation and modulation of pH in the brain. Physiol Rev. 2003;83:1183\u2013221.","journal-title":"Physiol Rev"},{"key":"8188_CR13","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.eplepsyres.2013.11.012","volume":"108","author":"X-F Yang","year":"2014","unstructured":"Yang X-F, Shi X-Y, Ju J, et al. 5% CO2 inhalation suppresses hyperventilation-induced absence seizures in children. Epilepsy Res. 2014;108:345\u20138.","journal-title":"Epilepsy Res"},{"key":"8188_CR14","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/nm1422","volume":"12","author":"S Schuchmann","year":"2006","unstructured":"Schuchmann S, Schmitz D, Rivera C, et al. Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med. 2006;12:817\u201323.","journal-title":"Nat Med"},{"key":"8188_CR15","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1111\/j.1528-1167.2011.03259.x","volume":"52","author":"S Schuchmann","year":"2011","unstructured":"Schuchmann S, Hauck S, Henning S, et al. Respiratory alkalosis in children with febrile seizures. Epilepsia. 2011;52:1949\u201355.","journal-title":"Epilepsia"},{"key":"8188_CR16","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1007\/s00540-005-0365-6","volume":"20","author":"S Sakurazawa","year":"2006","unstructured":"Sakurazawa S, Saito S, Yamada M, Nishihara F, Goto F. Carbon dioxide exhalation temporarily increases during electroconvulsive therapy. J Anesth. 2006;20:68\u201370.","journal-title":"J Anesth"},{"key":"8188_CR17","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1097\/YCT.0b013e3181620815","volume":"24","author":"E Sawayama","year":"2008","unstructured":"Sawayama E, Takahashi M, Inoue A, et al. Moderate hyperventilation prolongs electroencephalogram seizure duration of the first electroconvulsive therapy. J ECT. 2008;24:195\u20138.","journal-title":"J ECT"},{"key":"8188_CR18","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1002\/ana.22223","volume":"69","author":"MM Helmy","year":"2011","unstructured":"Helmy MM, Tolner EA, Vanhatalo S, Voipio J, Kaila K. Brain alkalosis causes birth asphyxia seizures, suggesting therapeutic strategy. Ann Neurol. 2011;69:493\u2013500.","journal-title":"Ann Neurol"},{"key":"8188_CR19","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1007\/s12031-014-0270-2","volume":"53","author":"W Guo","year":"2014","unstructured":"Guo W, Chen X, He JJ, et al. Down-regulated expression of acid-sensing ion channel 1a in cortical lesions of patients with focal cortical dysplasia. J Mol Neurosci. 2014;53:176\u201382.","journal-title":"J Mol Neurosci"},{"key":"8188_CR20","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1007\/BF00243215","volume":"101","author":"L Vel\u00edsek","year":"1994","unstructured":"Vel\u00edsek L, Dreier JP, Stanton PK, Heinemann U, Mosh\u00e9 SL. Lowering of extracellular pH suppresses low-Mg(2+)-induces seizures in combined entorhinal cortex-hippocampal slices. Exp Brain Res. 1994;101:44\u201352.","journal-title":"Exp Brain Res"},{"key":"8188_CR21","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1126\/science.123.3189.223","volume":"123","author":"WG Mitchell","year":"1956","unstructured":"Mitchell WG, Grubbs RC. Inhibition of audiogenic seizures by carbon dioxide. Science. 1956;123:223\u20134.","journal-title":"Science"},{"key":"8188_CR22","doi-asserted-by":"publisher","first-page":"3239","DOI":"10.1093\/brain\/awn277","volume":"131","author":"LM Bateman","year":"2008","unstructured":"Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain. 2008;131:3239\u201345.","journal-title":"Brain"},{"key":"8188_CR23","doi-asserted-by":"publisher","first-page":"335","DOI":"10.3389\/fncel.2018.00335","volume":"12","author":"R Kov\u00e1cs","year":"2018","unstructured":"Kov\u00e1cs R, Gerevich Z, Friedman A, et al. Bioenergetic mechanisms of seizure control. Front Cell Neurosci. 2018;12:335.","journal-title":"Front Cell Neurosci"},{"key":"8188_CR24","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1152\/jn.00915.2002","volume":"89","author":"J Voipio","year":"2003","unstructured":"Voipio J, Tallgren P, Heinonen E, Vanhatalo S, Kaila K. Millivolt-scale DC shifts in the human scalp EEG: evidence for a nonneuronal generator. J Neurophysiol. 2003;89:2208\u201314.","journal-title":"J Neurophysiol"},{"key":"8188_CR25","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1152\/jn.00110.2004","volume":"92","author":"DA Nita","year":"2004","unstructured":"Nita DA, Vanhatalo S, Lafortune F-D, Voipio J, Kaila K, Amzica F. Nonneuronal origin of CO 2-related DC EEG shifts: an in vivo study in the cat. J Neurophysiol. 2004;92:1011\u201322.","journal-title":"J Neurophysiol"},{"key":"8188_CR26","doi-asserted-by":"publisher","first-page":"e016181","DOI":"10.1136\/bmjopen-2017-016181","volume":"7","author":"P Ramnarayan","year":"2017","unstructured":"Ramnarayan P, Lister P, Dominguez T, et al. FIRST-line support for Assistance in Breathing in Children (FIRST-ABC): protocol for a multicentre randomised feasibility trial of non-invasive respiratory support in critically ill children. BMJ Open. 2017;7:e016181.","journal-title":"BMJ Open"},{"key":"8188_CR27","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s13063-022-06992-5","volume":"24","author":"M Iflaifel","year":"2023","unstructured":"Iflaifel M, Sprange K, Bell J, et al. Developing guidance for a risk-proportionate approach to blinding statisticians within clinical trials: a mixed methods study. Trials. 2023;24:71.","journal-title":"Trials"},{"key":"8188_CR28","unstructured":"Information Commissioner\u2019s Office. Anonymisation: managing data protection risk code of practice. 2012. Available from: https:\/\/ico.org.uk\/media\/1061\/anonymisation-code.pdf. Accessed 20 Dec 2023."},{"key":"8188_CR29","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1001\/jama.2017.18556","volume":"318","author":"C Gamble","year":"2017","unstructured":"Gamble C, Krishan A, Stocken D, et al. Guidelines for the content of statistical analysis plans in clinical trials. JAMA. 2017;318:2337\u201343.","journal-title":"JAMA"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08188-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-024-08188-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08188-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T06:05:04Z","timestamp":1716962704000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-024-08188-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,29]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["8188"],"URL":"https:\/\/doi.org\/10.1186\/s13063-024-08188-5","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,29]]},"assertion":[{"value":"9 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval for this study was granted by the North West Liverpool Central Research Ethics committee (ref 22\/NW\/0162). Written, informed consent to participate will be sought from all participants on an emergency deferred consent basis as described in this protocol.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate\u00a0{24}"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication\u00a0{32}"}},{"value":"KL is our patient and parent involvement representative and is a parent whose daughter has severe epilepsy and frequently experienced episodes of convulsive status epilepticus particularly when younger. We declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests\u00a0{28}"}}],"article-number":"349"}}