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BMC Neurology

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Open Access 01-12-2014 | Study protocol

Study protocol: prediction of stroke associated infections by markers of autonomic control

Authors: Dirk Brämer, Heike Hoyer, Albrecht Günther, Samuel Nowack, Frank M Brunkhorst, Otto W Witte, Dirk Hoyer

Published in: BMC Neurology | Issue 1/2014

Abstract

Background

Infection is the most important complication after acute stroke. This is substantially based on a stroke-induced immunosuppression. Heart rate variability (HRV) represents the autonomic nervous system activity in connection with stroke-induced immunomodulation and infections. We demonstrated in a feasibility study that HRV indices obtained in patients without acute post-stroke infections can predict infections in the subsequent sub-acute phase.

Methods/Design

The study PRED-SEP is a prospective observational study. Adult patients with acute ischemic infarction in the territory of the middle cerebral artery and severe neurological deficit (National Institutes of Health Stroke Scale: NIHSS ≥ 8) are recruited. Primary endpoint is the development of infections, secondary endpoints are SIRS and severe sepsis in the sub-acute phase (day 3–5) after stroke and the functional outcome after 3 months. Infection is defined according to the PANTHERIS study and comprises pneumonia, urinary tract infection and infections without determined focus. SIRS and severe sepsis are defined according to German Sepsis Society guidelines. Functional outcome is measured by lethality and neurological scores (modified Rankin Scale, Barthel Index). Prognostic factors are HRV risk indices calculated from selected intervals of 24 h ECG measurements within 48 hours after symptom onset. It is planned to recruit 240 patients.

HRV risk indices (predictors) will be calculated according to standards and procedures previously developed and published by the authors. The predictive effects of HRV indices on infections will be estimated by fitting logistic regression models and estimating odds ratios with 95% confidence intervals. A prespecified modelling procedure will be applied to estimate unadjusted and confounder adjusted odds ratios. Secondary endpoints will be analysed in the same way. The functional outcome scales will be dichotomized. The association between HRV indices and pro- and anti-inflammatory markers will be quantified by calculating the appropriate correlation coefficients according to scale (Person or Spearman).

Discussion

Since a general prophylactic antibiotic treatment after stroke is not recommended, results of this study could have essential implications for an early identification and hence, timely appropriate treating of stroke-induced infections.

Trial registration

Prädiktoren für die Sepsis - Pred Sep, German Clinical Trials Register: DRKS00003392.

Kumar S, Selim MH, Caplan LR: Medical complications after stroke. Lancet Neurol. 2010, 9 (1): 105-118. 10.1016/S1474-4422(09)70266-2.CrossRefPubMed

Hong KS, Kang DW, Koo JS, Yu KH, Han MK, Cho YJ, Park JM, Bae HJ, Lee BC: Impact of neurological and medical complications on 3-month outcomes in acute ischaemic stroke. Eur J Neurol. 2008, 15 (12): 1324-1331. 10.1111/j.1468-1331.2008.02310.x.CrossRefPubMed

Wartenberg KE, Stoll A, Funk A, Meyer A, Schmidt JM, Berrouschot J: Infection after acute ischemic stroke: risk factors, biomarkers, and outcome. Stroke Res Treatment. 2011, 2011: 830614-CrossRef

Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de Beek D: Post-stroke infection: a systematic review and meta-analysis. BMC Neurol. 2011, 11: 110-10.1186/1471-2377-11-110.CrossRefPubMedPubMedCentral

Diener W: Leitlinien für Diagnostik und Therapie in der Neurologie. 2012, Stuttgart: Thieme VerlagCrossRef

Emsley HC, Hopkins SJ: Acute ischaemic stroke and infection: recent and emerging concepts. Lancet Neurol. 2008, 7 (4): 341-353. 10.1016/S1474-4422(08)70061-9.CrossRefPubMed

Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U, et al: Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003, 198 (5): 725-736. 10.1084/jem.20021098.CrossRefPubMedPubMedCentral

Prass K, Braun JS, Dirnagl U, Meisel C, Meisel A: Stroke propagates bacterial aspiration to pneumonia in a model of cerebral ischemia. Stroke. 2006, 37 (10): 2607-2612. 10.1161/01.STR.0000240409.68739.2b.CrossRefPubMed

Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, Prass K, Meisel A: Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke. 2007, 38 (2 Suppl): 770-773.CrossRefPubMed

10.

Chamorro A, Urra X, Planas AM: Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke. 2007, 38 (3): 1097-1103. 10.1161/01.STR.0000258346.68966.9d.CrossRefPubMed

11.

Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U: Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005, 6 (10): 775-786.CrossRefPubMed

12.

Colivicchi F, Bassi A, Santini M, Caltagirone C: Cardiac autonomic derangement and arrhythmias in right-sided stroke with insular involvement. Stroke. 2004, 35 (9): 2094-2098. 10.1161/01.STR.0000138452.81003.4c.CrossRefPubMed

13.

Dutsch M, Burger M, Dorfler C, Schwab S, Hilz MJ: Cardiovascular autonomic function in poststroke patients. Neurology. 2007, 69 (24): 2249-2255. 10.1212/01.wnl.0000286946.06639.a7.CrossRefPubMed

14.

Chen PL, Kuo TB, Yang CC: Parasympathetic activity correlates with early outcome in patients with large artery atherosclerotic stroke. J Neurol Sci. 2012, 314 (1–2): 57-61.CrossRefPubMed

15.

Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF: Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J. 2004, 25 (5): 363-370. 10.1016/j.ehj.2003.12.003.CrossRefPubMed

16.

Janszky I, Ericson M, Lekander M, Blom M, Buhlin K, Georgiades A, Ahnve S: Inflammatory markers and heart rate variability in women with coronary heart disease. J Intern Med. 2004, 256 (5): 421-428. 10.1111/j.1365-2796.2004.01403.x.CrossRefPubMed

17.

Carney RM, Freedland KE, Stein PK, Miller GE, Steinmeyer B, Rich MW, Duntley SP: Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease. J Psychosom Res. 2007, 62 (4): 463-467. 10.1016/j.jpsychores.2006.12.004.CrossRefPubMedPubMedCentral

18.

Stein PK, Barzilay JI, Chaves PH, Traber J, Domitrovich PP, Heckbert SR, Gottdiener JS: Higher levels of inflammation factors and greater insulin resistance are independently associated with higher heart rate and lower heart rate variability in normoglycemic older individuals: the Cardiovascular Health Study. J Am Geriatr Soc. 2008, 56 (2): 315-321. 10.1111/j.1532-5415.2007.01564.x.CrossRefPubMed

19.

Haensel A, Mills PJ, Nelesen RA, Ziegler MG, Dimsdale JE: The relationship between heart rate variability and inflammatory markers in cardiovascular diseases. Psychoneuroendocrinology. 2008, 33 (10): 1305-1312. 10.1016/j.psyneuen.2008.08.007.CrossRefPubMedPubMedCentral

20.

Barnaby D, Ferrick K, Kaplan DT, Shah S, Bijur P, Gallagher EJ: Heart rate variability in emergency department patients with sepsis. Acad Emerg Med. 2002, 9 (7): 661-670. 10.1111/j.1553-2712.2002.tb02143.x.CrossRefPubMed

21.

Ahmad S, Ramsay T, Huebsch L, Flanagan S, McDiarmid S, Batkin I, McIntyre L, Sundaresan SR, Maziak DE, Shamji FM, et al: Continuous multi-parameter heart rate variability analysis heralds onset of sepsis in adults. PLoS One. 2009, 4 (8): e6642-10.1371/journal.pone.0006642.CrossRefPubMedPubMedCentral

22.

Schmidt H, Hoyer D, Hennen R, Heinroth K, Rauchhaus M, Prondzinsky R, Hottenrott K, Buerke M, Muller-Werdan U, Werdan K: Autonomic dysfunction predicts both 1- and 2-month mortality in middle-aged patients with multiple organ dysfunction syndrome. Crit Care Med. 2008, 36 (3): 967-970. 10.1097/CCM.0B013E3181653263.CrossRefPubMed

23.

Hoyer D, Friedrich H, Zwiener U, Pompe B, Baranowski R, Werdan K, Muller-Werdan U, Schmidt H: Prognostic impact of autonomic information flow in multiple organ dysfunction syndrome patients. Int J Cardiol. 2006, 108 (3): 359-369. 10.1016/j.ijcard.2005.05.031.CrossRefPubMed

24.

Hoyer D, Friedrich H, Frank B, Pompe B, Baranowski R, Zebrowski JJ, Schmidt H: Autonomic information flow improves prognostic impact of task force HRV monitoring. Comput Methods Programs Biomed. 2006, 81 (3): 246-255. 10.1016/j.cmpb.2006.01.002.CrossRefPubMed

25.

Gunther A, Salzmann I, Nowack S, Schwab M, Surber R, Hoyer H, Witte OW, Hoyer D: Heart rate variability - a potential early marker of sub-acute post-stroke infections. Acta Neurol Scand. 2012, 126: 189-196. 10.1111/j.1600-0404.2011.01626.x.CrossRefPubMed

26.

Harms H, Prass K, Meisel C, Klehmet J, Rogge W, Drenckhahn C, Gohler J, Bereswill S, Gobel U, Wernecke KD, et al: Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS ONE. 2008, 3 (5): e2158-10.1371/journal.pone.0002158.CrossRefPubMedPubMedCentral

27.

Hoyer D, Friedrich H, Stein PK, Domitrovich PP, Hoyer H, Faldu C, Buchman TG: Autonomic information flow improves prognostic value of heart rate patterns after abdominal aortic surgery. J Critical Care. 2008, 23 (2): 255-262. 10.1016/j.jcrc.2007.04.005.CrossRef

28.

Hoyer D, Maestri R, La Rovere MT, Pinna GD: Autonomic response to cardiac dysfunction in chronic heart failure: a risk predictor based on autonomic information flow. Pacing Clin Electrophysiol. 2008, 31 (2): 214-220. 10.1111/j.1540-8159.2007.00971.x.CrossRefPubMed

29.

Hoffmann S, Malzahn U, Harms H, Koennecke HC, Berger K, Kalic M, Walter G, Meisel A, Heuschmann PU, Berlin Stroke R, et al: Development of a clinical score (A2DS2) to predict pneumonia in acute ischemic stroke. Stroke. 2012, 43 (10): 2617-2623. 10.1161/STROKEAHA.112.653055.CrossRefPubMed

30.

Fluri F, Morgenthaler NG, Mueller B, Christ-Crain M, Katan M: Copeptin, procalcitonin and routine inflammatory markers-predictors of infection after stroke. PLoS One. 2012, 7 (10): e48309-10.1371/journal.pone.0048309.CrossRefPubMedPubMedCentral

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/14/9/prepub

Title: Study protocol: prediction of stroke associated infections by markers of autonomic control
Authors: Dirk Brämer
Heike Hoyer
Albrecht Günther
Samuel Nowack
Frank M Brunkhorst
Otto W Witte
Dirk Hoyer
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Neurology / Issue 1/2014
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/1471-2377-14-9

At a glance: The STEP trials

Springer Medicine

Study protocol: prediction of stroke associated infections by markers of autonomic control

Abstract

Background

Methods/Design

Discussion

Trial registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods/Design

Discussion

Trial registration

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