Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study

Claudine Angela Blum, Bettina Winzeler, Nicole Nigro, Philipp Schuetz, Silke Biethahn, Timo Kahles, Cornelia Mueller, Katharina Timper, Katharina Haaf, Janina Tepperberg, Margareth Amort, Andreas Huber, Roland Bingisser, Peter Stephan Sándor, Krassen Nedeltchev, Beat Müller, Mira Katan, Mirjam Christ-Crain, Claudine Angela Blum, Bettina Winzeler, Nicole Nigro, Philipp Schuetz, Silke Biethahn, Timo Kahles, Cornelia Mueller, Katharina Timper, Katharina Haaf, Janina Tepperberg, Margareth Amort, Andreas Huber, Roland Bingisser, Peter Stephan Sándor, Krassen Nedeltchev, Beat Müller, Mira Katan, Mirjam Christ-Crain

Abstract

Background: In the emergency setting, non-traumatic headache is a benign symptom in 80% of cases, but serious underlying conditions need to be ruled out. Copeptin improves risk stratification in several acute diseases. Herein, we investigated the value of copeptin to discriminate between serious secondary headache and benign headache forms in the emergency setting.

Methods: Patients presenting with acute non-traumatic headache were prospectively enrolled into an observational cohort study. Copeptin was measured upon presentation to the emergency department. Primary endpoint was serious secondary headache defined by a neurologic cause requiring immediate treatment of the underlying disease. Secondary endpoint was the combination of mortality and hospitalization within 3 months. Two board-certified neurologist blinded to copeptin levels verified the endpoints after a structured 3-month-telephone interview.

Results: Of the 391 patients included, 75 (19%) had a serious secondary headache. Copeptin was associated with serious secondary headache (OR 2.03, 95%CI 1.52-2.70, p < 0.0001). Area under the curve (AUC) for copeptin to identify the primary endpoint was 0.70 (0.63-0.76). After adjusting for age > 50, focal-neurological abnormalities, and thunderclap onset of symptoms, copeptin remained an independent predictive factor for serious secondary headache (OR 1.74, 95%CI 1.26-2.39, p = 0.001). Moreover, copeptin improved the AUC of the multivariate logistic clinical model (p-LR-test < 0.001). Even though copeptin values were higher in patients reaching the secondary endpoint, this association was not significant in multivariate logistic regression.

Conclusions: Copeptin was independently associated with serious secondary headache as compared to benign headaches forms. Copeptin may be a promising novel blood biomarker that should be further validated to rule out serious secondary headache in the emergency department.

Trial registration: Study Registration on 08/02/2010 as NCT01174901 at clinicaltrials.gov.

Keywords: Biomarker; Copeptin; Emergency; Head pain; Headache; Vasopressin.

Figures

Fig. 1
Fig. 1
STROBE study flow diagram
Fig. 2
Fig. 2
Boxplot of copeptin values

References

    1. Schuetz P, Christ-Crain M, Wolbers M, Schild U, Thomann R, Falconnier C, Widmer I, Neidert S, Blum CA, Schonenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Muller B, Pro Hsg Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial. BMC Health Serv Res. 2007;7:102. doi: 10.1186/1472-6963-7-102.
    1. Locker T, Mason S, Rigby A. Headache management--are we doing enough? An observational study of patients presenting with headache to the emergency department. Emerg Med J. 2004;21:327–332. doi: 10.1136/emj.2003.012351.
    1. Morgenstern LB, Huber JC, Luna-Gonzales H, Saldin KR, Grotta JC, Shaw SG, Knudson L, Frankowski RF. Headache in the emergency department. Headache. 2001;41:537–541. doi: 10.1046/j.1526-4610.2001.041006537.x.
    1. Stevenson RJ, Dutta D, MacWalter RS. The management of acute headache in adults in an acute admissions unit. Scott Med J. 1998;43:173–176. doi: 10.1177/003693309804300605.
    1. Ang SH, Chan YC, Mahadevan M. Emergency department headache admissions in an acute care hospital:why do they occur and what can we do about it? Ann Acad Med Singapore. 2009;38:1007–1010.
    1. Ramirez-Lassepas M, Espinosa CE, Cicero JJ, Johnston KL, Cipolle RJ, Barber DL. Predictors of intracranial pathologic findings in patients who seek emergency care because of headache. Arch Neurol. 1997;54:1506–1509. doi: 10.1001/archneur.1997.00550240058013.
    1. Grimaldi D, Nonino F, Cevoli S, Vandelli A, D’Amico R, Cortelli P. Risk stratification of non-traumatic headache in the emergency department. J Neurol. 2009;256:51–57. doi: 10.1007/s00415-009-0033-0.
    1. Cortelli P, Cevoli S, Nonino F, Baronciani D, Magrini N, Re G, De Berti G, Manzoni GC, Querzani P, Vandelli A. Evidence-based diagnosis of nontraumatic headache in the emergency department: a consensus statement on four clinical scenarios. Headache. 2004;44:587–595. doi: 10.1111/j.1526-4610.2004.446007.x.
    1. Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24 Suppl 1:9–160
    1. Holle D, Obermann M. The role of neuroimaging in the diagnosis of headache disorders. Ther Adv Neurol Disord. 2013;6:369–374. doi: 10.1177/1756285613489765.
    1. Locker TE, Thompson C, Rylance J, Mason SM. The utility of clinical features in patients presenting with nontraumatic headache: an investigation of adult patients attending an emergency department. Headache. 2006;46:954–961. doi: 10.1111/j.1526-4610.2006.00448.x.
    1. Breen DP, Duncan CW, Pope AE, Gray AJ, Al-Shahi Salman R. Emergency department evaluation of sudden, severe headache. QJM. 2008;101:435–443. doi: 10.1093/qjmed/hcn036.
    1. Loder E, Harrington MG, Cutrer M, Sandor P, De Vries B. Selected confirmed, probable, and exploratory migraine biomarkers. Headache. 2006;46:1108–1127. doi: 10.1111/j.1526-4610.2006.00525.x.
    1. Kosinski CM, Mull M, Schwarz M, Koch B, Biniek R, Schlafer J, Milkereit E, Willmes K, Schiefer J. Do normal D-dimer levels reliably exclude cerebral sinus thrombosis? Stroke. 2004;35:2820–2825. doi: 10.1161/01.STR.0000147045.71923.18.
    1. Guldiken S, Guldiken B, Demir M, Kabayel L, Ozkan H, Turgut N, Hunkar R, Kat S. Soluble CD40 ligand and prolactin levels in migraine patients during interictal period. J Headache Pain. 2011;12:355–360. doi: 10.1007/s10194-011-0306-8.
    1. Arulmani U, Maassenvandenbrink A, Villalon CM, Saxena PR. Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol. 2004;500:315–330. doi: 10.1016/j.ejphar.2004.07.035.
    1. Meng R, Wang X, Hussain M, Dornbos D, 3rd, Meng L, Liu Y, Wu Y, Ning M, Ferdinando SB, Lo EH, Ding Y, Ji X. Evaluation of plasma D-dimer plus fibrinogen in predicting acute CVST. Int J Stroke. 2014;9:166–173. doi: 10.1111/ijs.12034.
    1. Egea-Guerrero JJ, Revuelto-Rey J, Murillo-Cabezas F, Munoz-Sanchez MA, Vilches-Arenas A, Sanchez-Linares P, Dominguez-Roldan JM, Leon-Carrion J. Accuracy of the S100beta protein as a marker of brain damage in traumatic brain injury. Brain Inj. 2012;26:76–82. doi: 10.3109/02699052.2011.635360.
    1. Blyth BJ, Farhavar A, Gee C, Hawthorn B, He H, Nayak A, Stocklein V, Bazarian JJ. Validation of serum markers for blood–brain barrier disruption in traumatic brain injury. J Neurotrauma. 2009;26:1497–1507. doi: 10.1089/neu.2008.0738.
    1. Teepker M, Munk K, Mylius V, Haag A, Moller JC, Oertel WH, Schepelmann K. Serum concentrations of s100b and NSE in migraine. Headache. 2009;49:245–252. doi: 10.1111/j.1526-4610.2008.01228.x.
    1. Forcelini CM, Dantas DC, Luz C, Santin R, Stein AT, Barros HM, Barea LM. Analysis of leukocytes in medication-overuse headache, chronic migraine, and episodic migraine. Headache. 2011;51:1228–1238. doi: 10.1111/j.1526-4610.2011.01902.x.
    1. Durham P, Papapetropoulos S. Biomarkers associated with migraine and their potential role in migraine management. Headache. 2013;53:1262–1277. doi: 10.1111/head.12174.
    1. Widmer IE, Puder JJ, Konig C, Pargger H, Zerkowski HR, Girard J, Muller B. Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metab. 2005;90:4579–4586. doi: 10.1210/jc.2005-0354.
    1. Katan M, Muller B, Christ-Crain M. Copeptin: a new and promising diagnostic and prognostic marker. Crit Care. 2008;12:117. doi: 10.1186/cc6799.
    1. Katan M, Christ-Crain M. The stress hormone copeptin: a new prognostic biomarker in acute illness. Swiss Med Wkly. 2010;140:w13101.
    1. Friedman BW, Hochberg ML, Esses D, Grosberg B, Corbo J, Toosi B, Meyer RH, Bijur PE, Lipton RB, Gallagher EJ. Applying the International Classification of Headache Disorders to the emergency department: an assessment of reproducibility and the frequency with which a unique diagnosis can be assigned to every acute headache presentation. Ann Emerg Med. 2007;49:409–419. doi: 10.1016/j.annemergmed.2006.11.004.
    1. Marlow RA, Kegowicz CL, Starkey KN. Prevalence of depression symptoms in outpatients with a complaint of headache. J Am Board Fam Med. 2009;22:633–637. doi: 10.3122/jabfm.2009.06.070098.
    1. Lipton RB, Stewart WF, Sawyer J, Edmeads JG. Clinical utility of an instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Headache. 2001;41:854–861. doi: 10.1046/j.1526-4610.2001.01156.x.
    1. Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H, Morgenthaler NG, Bergmann A, Potocki M, Noveanu M, Breidthardt T, Christ A, Boldanova T, Merki R, Schaub N, Bingisser R, Christ M, Mueller C. Incremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Coll Cardiol. 2009;54:60–68. doi: 10.1016/j.jacc.2009.01.076.
    1. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem. 2006;52:112–119. doi: 10.1373/clinchem.2005.060038.
    1. Katan M, Fluri F, Morgenthaler NG, Schuetz P, Zweifel C, Bingisser R, Muller K, Meckel S, Gass A, Kappos L, Steck AJ, Engelter ST, Muller B, Christ-Crain M. Copeptin: a novel, independent prognostic marker in patients with ischemic stroke. Ann Neurol. 2009;66:799–808. doi: 10.1002/ana.21783.
    1. Zweifel C, Katan M, Schuetz P, Siegemund M, Morgenthaler NG, Merlo A, Mueller B, Christ-Crain M. Copeptin is associated with mortality and outcome in patients with acute intracerebral hemorrhage. BMC Neurol. 2010;10:34. doi: 10.1186/1471-2377-10-34.
    1. Kruger S, Ewig S, Kunde J, Hanschmann A, Marre R, Suttorp N, Welte T. C-terminal provasopressin (copeptin) in patients with community-acquired pneumonia--influence of antibiotic pre-treatment: results from the German competence network CAPNETZ. J Antimicrob Chemother. 2009;64:159–162. doi: 10.1093/jac/dkp148.
    1. Seligman R, Papassotiriou J, Morgenthaler NG, Meisner M, Teixeira PJ. Copeptin, a novel prognostic biomarker in ventilator-associated pneumonia. Crit Care. 2008;12:R11. doi: 10.1186/cc6780.
    1. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143:29–36. doi: 10.1148/radiology.143.1.7063747.
    1. Jensen MB, Chacon MR, Sattin JA, Aleu A, Lyden PD. The promise and potential pitfalls of serum biomarkers for ischemic stroke and transient ischemic attack. Neurologist. 2008;14:243–246. doi: 10.1097/NRL.0b013e31815a9945.
    1. Vickers AJ, Cronin AM, Begg CB. One statistical test is sufficient for assessing new predictive markers. BMC Med Res Methodol. 2011;11:13. doi: 10.1186/1471-2288-11-13.
    1. L’Abate P, Wiegert S, Struck J, Wellmann S, Cannizzaro V. Determinants of plasma copeptin: a systematic investigation in a pediatric mechanical ventilation model. Respir Physiol Neurobiol. 2013;185:222–227. doi: 10.1016/j.resp.2012.10.011.
    1. Morgenthaler NG, Muller B, Struck J, Bergmann A, Redl H, Christ-Crain M. Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock. Shock. 2007;28:219–226. doi: 10.1097/SHK.0b013e318033e5da.
    1. Muller B, Morgenthaler N, Stolz D, Schuetz P, Muller C, Bingisser R, Bergmann A, Tamm M, Christ-Crain M. Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections. Eur J Clin Invest. 2007;37:145–152. doi: 10.1111/j.1365-2362.2007.01762.x.
    1. Katan M, Morgenthaler N, Widmer I, Puder JJ, Konig C, Muller B, Christ-Crain M. Copeptin, a stable peptide derived from the vasopressin precursor, correlates with the individual stress level. Neuro Endocrinol Lett. 2008;29:341–346.
    1. Aliberti S, Di Pasquale M, Zanaboni AM, Cosentini R, Brambilla AM, Seghezzi S, Tarsia P, Mantero M, Blasi F. Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia. Clin Infect Dis. 2012;54:470–478. doi: 10.1093/cid/cir840.
    1. Riquelme R, Jimenez P, Videla AJ, Lopez H, Chalmers J, Singanayagam A, Riquelme M, Peyrani P, Wiemken T, Arbo G, Benchetrit G, Rioseco ML, Ayesu K, Klotchko A, Marzoratti L, Raya M, Figueroa S, Saavedra F, Pryluka D, Inzunza C, Torres A, Alvare P, Fernandez P, Barros M, Gomez Y, Contreras C, Rello J, Bordon J, Feldman C, Arnold F, Nakamatsu R, Riquelme J, Blasi F, Aliberti S, Cosentini R, Lopardo G, Gnoni M, Welte T, Saad M, Guardiola J, Ramirez J. Predicting mortality in hospitalized patients with 2009 H1N1 influenza pneumonia. Int J Tuberc Lung Dis. 2011;15:542–546. doi: 10.5588/ijtld.10.0539.
    1. Torres A, Blasi F, Peetermans WE, Viegi G, Welte T. The aetiology and antibiotic management of community-acquired pneumonia in adults in Europe: a literature review. Eur J Clin Microbiol Infect Dis. 2014;33:1065–1079. doi: 10.1007/s10096-014-2067-1.
    1. Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, Serrano D, Lipton RB. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013;53:1278–1299. doi: 10.1111/head.12150.
    1. Charles PG, Whitby M, Fuller AJ, Stirling R, Wright AA, Korman TM, Holmes PW, Christiansen KJ, Waterer GW, Pierce RJ, Mayall BC, Armstrong JG, Catton MG, Nimmo GR, Johnson B, Hooy M, Grayson ML. The etiology of community-acquired pneumonia in Australia: why penicillin plus doxycycline or a macrolide is the most appropriate therapy. Clin Infect Dis. 2008;46:1513–1521. doi: 10.1086/586749.
    1. Ananda-Rajah MR, Charles PG, Melvani S, Burrell LL, Johnson PD, Grayson ML. Comparing the pneumonia severity index with CURB-65 in patients admitted with community acquired pneumonia. Scand J Infect Dis. 2008;40:293–300. doi: 10.1080/00365540701663381.
    1. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4:e296. doi: 10.1371/journal.pmed.0040296.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit