Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot Password? Reset your password

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login (Shibboleth)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Journal Mobile Options
Table of Contents
Vol. 33, No. 6, 2012
Issue release date: June 2012
Section title: Translational Research in Stroke
Free Access
Cerebrovasc Dis 2012;33:580–588
(DOI:10.1159/000338080)

Predicting Post-Stroke Infections and Outcome with Blood-Based Immune and Stress Markers

Meisel A.a · Meisel C.b · Harms H.a · Hartmann O.c · Ulm L.a
aNeurocure Clinical Research Center, Department of Neurology and Center for Stroke Research Berlin, and bDepartment of Medical Immunology, Charité – Universitätsmedizin Berlin, Berlin, and cThermo Fisher Scientific BRAHMS GmbH, Hennigsdorf, Germany
email Corresponding Author

Andreas Meisel

Department of Neurology, Charité – Universitätsmedizin Berlin

Charitéplatz 1

DE–10117 Berlin (Germany)

Tel. +49 30 450 560 026, E-Mail andreas.meisel@charite.de


Abstract

About one third of early deaths and poor outcomes after acute stroke are caused by potentially preventable stroke-associated complications, especially infections. Early identification of patients at high risk of infections and poor prognosis with biomarkers might help to initiate adequate therapies and guide treatment decisions. Acute injury of the central nervous system, including stroke, disturbs the normally well-balanced interplay between the sympathetic nervous system and the immune system, thereby impairing the antibacterial immune response in stroke patients. Changes in immune and stress markers, for example a reduction in HLA-DR expression on monocytes or an increase in serum catecholamine levels, occur very early after stroke onset, explain the high susceptibility of stroke patients to bacterial infections, and are predictive of infectious complications occurring up to 2 weeks after stroke. Outcome prediction is of utmost importance for decision-making in stroke units as well as in neurological intensive care units. However, to date the accuracy of outcome prediction by physicians and clinical scoring systems is only moderate. So far, only two blood-based biomarkers have been identified as independent predictors of outcome and mortality after stroke: the stress marker copeptin and midregional pro-atrial natriuretic peptide. Careful evaluation of prognostic markers is needed to prevent the occurrence of self-fulfilling prophecy.

© 2012 S. Karger AG, Basel


Related Articles for ""

Close Related Articles


Background

Stroke is one of the leading causes of severe long-term disability and death worldwide [1]. Prognosis after stroke is highly variable and depends on patient-related factors, such as stroke severity and age, but also on potentially preventable stroke-associated complications, like increased intracranial pressure and infections [2,3], which account for one third of all in-hospital deaths after ischaemic stroke [3]. Among post-stroke infections, bacterial pneumonia is of particular importance, as it causes almost 20% of in-hospital deaths after stroke [4,5,6,7] and has a negative impact on long-term outcome [3,8,9].

Underlying infections are the most common cause of fever after stroke [10]. Pyrexia after stroke is independently associated with an increased risk of poor outcome, particularly in patients who have an early rise in body temperature after stroke [11]. On the other hand, induced hypothermia is known to have neuroprotective properties and to improve outcome, for example after resuscitation [12]. These observations imply that early cooling of patients might be effective in improving outcome after stroke. However, hypothermia is also known to suppress the immune system, and acute-stroke patients treated with hypothermia had increased rates of pneumonia [13]. Up to now, cooling awake patients to 35°C after ischaemic stroke has been shown to be safe, but whether this improves functional outcome has not yet been tested in an adequately sized randomized clinical trial [14]. Hence, the upcoming EuroHYP trial, which is a European, multicenter, open, randomized, phase III clinical trial, will assess the effects of therapeutic cooling in 1,500 awake adult patients with acute ischaemic stroke.

As post-stroke infections have been shown to be associated with poor outcome in animal models of stroke and in human trials [2,15], the question arises whether preventive antibiotic treatment may not only reduce the incidence of infections, but also improve overall outcome. Indeed, in a preclinical stroke model, prophylactic antibiotic treatment prevented infections and improved outcome [16]. A recent meta-analysis of all published trials investigating the effects of prophylactic antibiotic treatment in acute-stroke patients concluded that this treatment strategy is effective in preventing post-stroke infections, but does not reduce mortality [17]. However, as all of these clinical trials were not sufficiently powered to investigate the impact of a preventive antibiotic treatment on outcome, the observed effects need to be evaluated in large trials that include patients at risk of post-stroke infections. Table 1 summarizes recently finalized or ongoing clinical trials aimed at treating post-stroke infections by antibiotic therapy.

Table 1

Summary of recently finalized or ongoing clinical trials aimed at treating post-stroke infections

http://www.karger.com/WebMaterial/ShowPic/204186

A major drawback of preventive antibacterial therapy is the potential promotion of antibiotic resistance in common bacteria, since increased use of antibiotics can increase resistance rates. Biomarkers might help to select patients who need antibiotic therapy (fig. 1), thereby lowering the risk of increased resistance rates. Furthermore, they might provide information on a patient’s prognosis early after stroke, which might be important to guide treatment decisions. In a patient who is expected to have a good outcome, early treatment of complications (e.g. infections) might be desirable to ensure his or her good probability of improvement. On the other hand, for patients in whom a reduction of therapeutic efforts is considered, reliable prognostic information would be helpful to assist families and physicians in their difficult decision.

Fig. 1

Biomarkers might help to identify patients at risk of poor outcome and infections early after stroke, thereby providing important information for clinical practice.

http://www.karger.com/WebMaterial/ShowPic/204184

Biomarkers are defined as biological, biochemical, or biophysical parameters that can be monitored objectively and reproducibly in humans or animal models [18]. Several categories of biomarkers have been studied with regard to their power to predict complications and outcome after stroke, e.g. physical markers like body temperature or blood glucose [19,20], imaging markers including perfusion- and diffusion-weighted imaging (PWI/DWI) of lesion volumes [21], and blood or cerebrospinal fluid markers. Among the latter, immune and inflammatory markers and proteins involved in cerebral and cardiac tissue damage or haemostasis are under investigation [22]. The levels of the neuronal and glial damage markers neuron-specific enolase (NSE) and S100-β, for example, have been demonstrated to correlate with infarct volume [23]. Moreover, high levels of fibrinogen have been associated with poor outcome 3 months after stroke [24]. In the following review, we will focus on blood-based immune and stress markers predicting outcome and infections after stroke and their implications for clinical care.

Immune and Stress Markers for the Prediction of Post-Stroke Infections

Even in specialized stroke units, post-stroke infections remain one of the main complications in acute stroke, with frequencies between 21 and 65% [2]. A number of predisposing factors are considered to account for the high incidence of bacterial pneumonia following stroke, including several factors known to facilitate aspiration, such as impaired protective reflexes, dysphagia and mechanical ventilation [4,6,25]. In addition, experimental and clinical evidence suggests that acute central nervous system injury, including stroke, directly impairs antibacterial host defence, thereby increasing susceptibility to infections [26,27,28,29]. In particular, down-regulation of systemic cellular immune responses, i.e. a rapid numerical decrease in peripheral blood lymphocyte subpopulations and functional deactivation of monocytes (fig. 2), T helper and invariant natural killer T cells [30], has been reported. Furthermore, signs of immunodepression are more prominent and recover more slowly in patients who develop infectious complications [27,31,32,33,34,35]. Importantly, reduced monocytic HLA-DR expression on day 1 after stroke onset was a strong independent predictor of subsequent post-stroke infections in the PANTHERIS trial [31]. In this trial, infections occurred between day 2 and day 7 after stroke onset; on average, both pneumonia and urinary tract infections were diagnosed on day 5. Moreover, changes in immune markers on day 1 after stroke, like reduced monocytic HLA-DR expression or low CD4+ T cell counts, independently predicted subsequent post-stroke infections developing within 2 weeks after stroke [31,35].

Fig. 2

Acute central nervous system damage reduces MHC II expression on monocytes via two mechanisms: it decreases the production of IFN-γ, which normally enhances MHC II expression, and increases IL-10, TGF-β and stress hormone levels, which suppress MHC II expression.

http://www.karger.com/WebMaterial/ShowPic/204183

Acute central nervous system injury, including stroke or traumatic brain injury, disturbs the normally well-balanced interplay between the nervous and the immune system by compromising sympathetic and parasympathetic neural connections with lymphoid organs and humoural components, including the hypothalamo-pituitary-adrenal axis [2,36,37]. A key role of the sympathetic nervous system in impaired antibacterial immune response after stroke has been shown in a mouse model of focal cerebral ischaemia: in that model, impaired lymphocyte responses and increased susceptibility to bacterial infections could be effectively prevented by blocking the sympathetic nervous system [15,30,38]. Moreover, Chamorro et al. [37] demonstrated that the development of infections early after acute ischaemic stroke is associated with enhanced activation of the sympathetic adrenomedullar pathway as indicated by significantly increased plasma catecholamine levels on day 1 after stroke in patients who subsequently (days 2–7) developed infections [37]. Similarly, in the PANTHERIS trial [31], patients with infections in the placebo group had significantly higher urine norepinephrine levels on day 1 and 2 after stroke compared to patients without infections [39]. These clinical findings support the concept of a stress-mediated immunodepression driven by the sympathetic nervous system and hypothalamo-pituitary axis as an essential facilitating factor for the development of post-stroke infections.

These findings might also have implications for the treatment of post-stroke infections. Selective immunomodulation to prevent post-stroke infections may be an alternative to preventive antibiotic treatment [40]. For example, administration of α-galactosylceramide, an activator of invariant natural killer T cells, increased systemic interferon-γ (IFN-γ) levels, and reduced bacterial infections and lung damage after experimental stroke in mice [30]. Likewise, systemic application of IFN-γ prevented post-stroke infections in an experimental stroke model [15]. To our knowledge, only one drug with known immunomodulatory properties, i.e. granulocyte colony-stimulating factor (G-CSF), has been investigated in clinical trials of acute stroke treatment. G-CSF is a haematopoietic cytokine responsible for the mobilization and differentiation of haematopoietic stem cells. It is in widespread clinical use to mobilize stem cells for transplantation in patients with haematological malignancies or for the treatment of chemotherapy-associated neutropenia. In addition to its effects on the haematopoietic system, G-CSF has also been shown to have neuroprotective and neurotrophic properties in experimental stroke models [41]. In the multicenter, randomized, placebo-controlled phase IIa trial AXIS, the safety and tolerability of intravenous G-CSF treatment have been tested in 44 acute ischaemic stroke patients. G-CSF led to a significant increase in neutrophils and monocytes [42]. The subsequent randomized, double-blind AXIS 2 trial, which included 328 stroke patients, failed to demonstrate an improvement of 3-month outcome by G-CSF treatment (press release of SYGNIS Pharma AG, December 15, 2011). The effects on post-stroke infections were reported in neither trial.

In summary, changes in immune and stress markers occur very early after stroke onset, explain the high susceptibility of stroke patients to bacterial infections, and are able to predict infectious complications occurring within 2 weeks after stroke (table 2). Further research is needed to better understand the mechanisms of brain-immune interaction after acute brain injury, and the long-term consequences immunomodulatory therapies may have for stroke outcome [40].

Table 2

Summary of blood-based immune and stress markers for predicting post-stroke infections in mice and humans

http://www.karger.com/WebMaterial/ShowPic/204185

Immune and Stress Markers for the Prediction of Long-Term Outcome in Stroke

The National Institutes of Health Stroke Scale (NIHSS) is a quantitative assessment of stroke-related neurological deficits. It can be performed quickly [43] and with high reliability and validity [44]. Originally developed for use in acute-stroke therapy trials [43,45], it has been shown to have predictive capacity concerning functional outcome up to 6 months after stroke [46]. Several blood-based inflammation markers, like C-reactive protein [47,48], high-sensitive C-reactive protein [49,50], white blood cell count [34], monocyte chemotactic protein-1 [51] or interleukin-6 [52], have also been associated with outcome, but all of them failed to improve the prognostic capacity of the NIHSS, which limits their clinical relevance. A role of the innate immune system in outcome prediction has recently been demonstrated: the monocyte subtype CD14highCD16 and higher expression of Toll-like receptor 4 in monocytes were independently associated with poor prognosis in acute stroke patients [53,54], and deficiency of mannose-binding lectin, a complement activator, was independently associated with better outcome in experimental and human stroke [55].

Stress-responsive cytokines are induced after stroke and might predict outcome. For example, elevated serum concentrations of growth differentiation factor 15 are associated with an unfavourable outcome after ischaemic stroke [56]. To date, there are only two stress markers that independently predict functional outcome and mortality: copeptin, a fragment of provasopressin, and midregional pro-atrial natriuretic peptide (MR-proANP). Blood levels of the stress marker copeptin upon admission (0–72 h after symptom onset) predicted functional outcome and mortality within 90 days similarly to the NIHSS (c-index of 0.82 for mortality and 0.73 for outcome). In multivariate logistic regression analysis including known outcome predictors such as the NIHSS, age and female sex, copeptin remained an independent predictor of an unfavourable functional outcome and mortality [57]. Even in a 1-year follow-up of the same patient cohort, the initial copeptin concentrations independently predicted functional outcome and death [58]. MR-proANP can be seen as an indirect stress marker, as higher levels of natriuretic peptides in stroke patients are associated with increased sympathetic activation [59]. Elevation of MR-proANP upon admission (0–72 h after symptom onset) was strongly associated with mortality and poor functional outcome at day 90 after stroke (c-index of 0.86 for mortality and 0.70 for outcome). Models incorporating copeptin or MR-pro-ANP and the NIHSS even improved their accuracy in the prediction of an unfavourable outcome or mortality [57,59]. The predictive capacity of copeptin and MR-proANP was further corroborated by the PANTHERIS trial [31]: Copeptin and MR-proANP levels 3 days after stroke showed high sensitivity and specificity in the prediction of poor outcome (death or Barthel Index <20) 90 days after stroke (c-index 0.83 and 0.79, respectively).

However, some blood-based biomarkers, such as interleukin-6 or N-terminal pro-brain natriuretic peptide, might not have sufficient predictive power to be of clinical use to predict poor outcome after stroke [60,61]. A sensitive and specific prediction of outcome is of paramount importance in the management of critically ill patients, in whom decisions about life-sustaining therapies are made. These include decisions not to institute therapies that would otherwise be warranted (withholding) and decisions about the discontinuation of treatments that had been started (withdrawing). Withholding and withdrawing treatments are considered legally and ethically equivalent [62], although this is in conflict with social or psychological convictions that they are different acts [62] and they might have different implications for clinical care, e.g. regarding the importance of consent [63] or their potential impact on patients’ outcome [64].

Decisions to forgo treatment in intensive care units have been shown to be associated with several factors, including higher age of the patients, the severity of their illness, pre-existing severe medical conditions, physicians’ and patients’ religious affiliation, patients’ wishes, and the physicians’ prediction of a low likelihood of survival and poor future functional outcome [64,65,66,67,68]. Especially the latter is a strong determinant of life support limitation. Outcome prediction (chances of recovery, expected time course of recovery and anticipated quality of life) influences treatment decisions of physicians [64,69,70,71] and is the most important criterion for patients and their relatives to make a decision of treatment withdrawal [67,72] – although the accuracy of early outcome prediction by physicians or currently used scoring systems, e.g. the Acute Physiology and Chronic Health Evaluation Score (APACHE) II, is only moderate [73]. Against this background, the development of sensitive and specific biomarkers to improve outcome prediction is of great importance for clinical practice and an important research field. A number of genes involved in immune regulation and inflammatory responses show characteristic changes in their expression pattern after stroke; these changes precede infections, and a bad functional outcome and death (fig. 3, 4). However, before turning these immune markers into useful tools for clinical practice, some questions still have to be answered. First, one has to be sure that changes in inflammation markers used to predict outcome are independent of the occurrence of complications, e.g. infections that influence the outcome negatively [74]. Furthermore, cut-off values of biomarkers are presumably affected by multiple parameters, as is seen with neuron specific enolase (NSE). In comatose survivors after cardiopulmonary resuscitation, NSE levels exceeding 33 µg/l were an established predictor of poor outcome [75,76]. With the introduction of the novel treatment approach of therapeutic hypothermia, the previously validated cut-off levels were not useful anymore, as survivors undergoing hypothermia treatment had markedly higher NSE cut-off levels for a bad outcome compared to non-hypothermia patients [77,78].

Fig. 3

Agilent Whole Human Genome Oligo Microarray kit of peripheral blood mononuclear cells (day 1 and day 3) derived from study participants of the PANTHERIS trial showing an up to 4-fold up-regulation (red) and down-regulation (green) of genes involved in immune regulation and inflammatory responses in the group of infected patients.

http://www.karger.com/WebMaterial/ShowPic/204182

Fig. 4

Agilent Whole Human Genome Oligo Microarray kit of peripheral blood mononuclear cells (day 1 and day 3) derived from study participants of the PANTHERIS trial showing an up to 4-fold up-regulation (red) and down-regulation (green) of genes involved in immune regulation and inflammatory responses in the group of patients who had a bad functional outcome or died.

http://www.karger.com/WebMaterial/ShowPic/204181

A reduction in the number of therapeutic procedures based on biomarkers that predict a bad outcome has to be evaluated carefully to prevent the creation of self-fulfilling prophecy. If, for example, antimicrobial therapy is withheld in patients who are considered to be at high risk of having a bad outcome, this may lead to a higher probability of bad outcomes in these patients – whether or not the initial prediction was correct. But as the rate of bad outcomes will then be higher in the group which was expected to have a bad outcome, the prediction will be believed to be true.

In conclusion, blood-based immune and stress markers might identify patients at high risk of post-stroke infections as well as patients with unfavourable outcomes. Thus, biomarker guidance is a promising strategy to tailor preventive treatment of post-stroke infections, thereby improving long-term outcomes. However, further clinical studies for the characterization of prognostic markers are needed to provide clinicians with reliable information.

Acknowledgement

We thank Stephanie Ohlraun for her valuable comments on the manuscript. This work was supported by the German Research Foundation (Exc 257), the Federal Ministry of Education and Research (01 EO 08 01), the Helmholtz Association (SO-022NG) and has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 201024 (all given to A.M.).

Disclosure Statement

C.M. and H.H. have received speaker’s honoraria from Bayer Vital GmbH. A.M. has received speaker’s honoraria from Bayer Vital GmbH and Wyeth Pharma GmbH. A patent application on anti-infective agents and immunomodulators used for preventive therapy following an acute cerebrovascular accident has been filed to the European Patent Office (PCT/EP03/02246) (patent owner Charité – Universitätsmedizin Berlin, inventor A.M., C.M.). O.H. is employed as a biostatistician by Thermo Fisher Scientific Brahms GmbH, Germany.


References

  1. Mathers CD, Boerma T, Ma Fat D: Global and regional causes of death. Br Med Bull 2009;92:7–32.
    External Resources
  2. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U: Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 2005;6:775–786.
  3. Koennecke HC, Belz W, Berfelde D, Endres M, Fitzek S, Hamilton F, Kreitsch P, Mackert BM, Nabavi DG, Nolte CH, Pohls W, Schmehl I, Schmitz B, von Brevern M, Walter G, Heuschmann PU: Factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit. Neurology 2011;77:965–972.
    External Resources
  4. Hilker R, Poetter C, Findeisen N, Sobesky J, Jacobs A, Neveling M, Heiss WD: Nosocomial pneumonia after acute stroke: implications for neurological intensive care medicine. Stroke 2003;34:975–981.
  5. Langhorne P, Stott DJ, Robertson L, MacDonald J, Jones L, McAlpine C, Dick F, Taylor GS, Murray G: Medical complications after stroke: a multicenter study. Stroke 2000;31:1223–1229.
  6. Katzan IL, Cebul RD, Husak SH, Dawson NV, Baker DW: The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology 2003;60:620–625.
  7. Aslanyan S, Weir CJ, Diener HC, Kaste M, Lees KR: Pneumonia and urinary tract infection after acute ischaemic stroke: a tertiary analysis of the GAIN International trial. Eur J Neurol 2004;11:49–53.
  8. 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;15:1324–1331.
  9. Wartenberg KE, Stoll A, Funk A, Meyer A, Schmidt JM, Berrouschot J: Infection after acute ischemic stroke: risk factors, biomarkers, and outcome. Stroke Res Treat 2011;2011:830614.
    External Resources
  10. Kumar S, Selim MH, Caplan LR: Medical complications after stroke. Lancet Neurol 2010;9:105–118.
  11. Polderman KH: Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955–1969.
    External Resources
  12. van der Worp HB, Macleod MR, Kollmar R: Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab 2010;30:1079–1093.
  13. Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD: Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 2010;41:2265–2270.
  14. Meisel A: Effective fever control in acute stroke: still wanted! Cerebrovasc Dis 2011;31:390–391.
  15. Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U, Volk HD, Meisel A: 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;198:725–736.
  16. Meisel C, Prass K, Braun J, Victorov I, Wolf T, Megow D, Halle E, Volk HD, Dirnagl U, Meisel A: Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke. Stroke 2004;35:2–6.
  17. Westendorp WF, Vermeij JD, Vermeij F, Den Hertog HM, Dippel DW, van de Beek D, Nederkoorn PJ: Antibiotic therapy for preventing infections in patients with acute stroke. Cochrane Database Syst Rev 2012;1:CD008530.
  18. Feuerstein GZ, Chavez J: Translational medicine for stroke drug discovery: the pharmaceutical industry perspective. Stroke 2009;40(3 Suppl):S121–125.
    External Resources
  19. Bruno A, Biller J, Adams HP, Jr., Clarke WR, Woolson RF, Williams LS, Hansen MD: Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology 1999;52:280–284.
  20. Hajat C, Hajat S, Sharma P: Effects of poststroke pyrexia on stroke outcome: a meta-analysis of studies in patients. Stroke 2000;31:410–414.
  21. Nuutinen J, Liu Y, Laakso MP, Karonen JO, Roivainen R, Vanninen RL, Partanen K, Ostergaard L, Sivenius J, Aronen HJ: Assessing the outcome of stroke: a comparison between MRI and clinical stroke scales. Acta Neurol Scand 2006;113:100–107.
  22. Whiteley W, Chong WL, Sengupta A, Sandercock P: Blood markers for the prognosis of ischemic stroke: a systematic review. Stroke 2009;40:e380–e389.
  23. Ahmad O, Wardlaw J, Whiteley WN: Correlation of levels of neuronal and glial markers with radiological measures of infarct volume in ischaemic stroke: a systematic review. Cerebrovasc Dis 2012;33:47–54.
  24. Hasan N, McColgan P, Bentley P, Edwards RJ, Sharma P: Towards the identification of blood biomarkers for acute stroke in humans: a comprehensive systematic review. Br J Clin Pharmacol 2012, E-pub ahead of print.
  25. Nakajoh K, Nakagawa T, Sekizawa K, Matsui T, Arai H, Sasaki H: Relation between incidence of pneumonia and protective reflexes in post-stroke patients with oral or tube feeding. J Intern Med 2000;247:39–42.
  26. 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(suppl 2):770–773.
    External Resources
  27. Chamorro A, Urra X, Planas AM: Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke 2007;38:1097–1103.
  28. Emsley HC, Hopkins SJ: Acute ischaemic stroke and infection: recent and emerging concepts. Lancet Neurol 2008;7:341–353.
  29. Dziedzic T, Slowik A, Szczudlik A: Nosocomial infections and immunity: lesson from brain-injured patients. Crit Care 2004;8:266–270.
    External Resources
  30. Wong CH, Jenne CN, Lee WY, Leger C, Kubes P: Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 2011;334:101–105.
  31. Harms H, Prass K, Meisel C, Klehmet J, Rogge W, Drenckhahn C, Gohler J, Bereswill S, Gobel U, Wernecke KD, Wolf T, Arnold G, Halle E, Volk HD, Dirnagl U, Meisel A: Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One 2008;3:e2158.
  32. Haeusler KG, Schmidt WU, Fohring F, Meisel C, Helms T, Jungehulsing GJ, Nolte CH, Schmolke K, Wegner B, Meisel A, Dirnagl U, Villringer A, Volk HD: Cellular immunodepression preceding infectious complications after acute ischemic stroke in humans. Cerebrovasc Dis 2008;25:50–58.
  33. Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Torres F, Planas AM: Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke. J Neurol Neurosurg Psychiatry 2006;77:1279–1281.
  34. Czlonkowska A, Ryglewicz D, Lechowicz W: Basic analytical parameters as the predictive factors for 30-day case fatality rate in stroke. Acta Neurol Scand 1997;95:121–124.
  35. Vogelgesang A, Grunwald U, Langner S, Jack R, Broker BM, Kessler C, Dressel A: Analysis of lymphocyte subsets in patients with stroke and their influence on infection after stroke. Stroke 2008;39:237–241.
  36. Woiciechowsky C, Asadullah K, Nestler D, Eberhardt B, Platzer C, Schoning B, Glockner F, Lanksch WR, Volk HD, Docke WD: Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 1998;4:808–813.
  37. Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Gomez-Choco M, Torres F, Planas AM: Catecholamines, infection, and death in acute ischemic stroke. J Neurol Sci 2007;252:29–35.
  38. Prass K, Braun JS, Dirnagl U, Meisel C, Meisel A: Stroke propagates bacterial aspiration to pneumonia in a model of cerebral ischemia. Stroke 2006;37:2607–2612.
  39. Harms H, Reimnitz P, Bohner G, Werich T, Klingebiel R, Meisel C, Meisel A: Influence of stroke localization on autonomic activation, immunodepression, and post-stroke infection. Cerebrovasc Dis 2011;32:552–560.
  40. Meisel C, Meisel A: Suppressing immunosuppression after stroke. N Engl J Med 2011;365:2134–2136.
  41. Schabitz WR, Kruger C, Pitzer C, Weber D, Laage R, Gassler N, Aronowski J, Mier W, Kirsch F, Dittgen T, Bach A, Sommer C, Schneider A: A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF). J Cereb Blood Flow Metab 2008;28:29–43.
    External Resources
  42. Schabitz WR, Laage R, Vogt G, Koch W, Kollmar R, Schwab S, Schneider D, Hamann GF, Rosenkranz M, Veltkamp R, Fiebach JB, Hacke W, Grotta JC, Fisher M, Schneider A: AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 2010;41:2545–2551.
    External Resources
  43. Brott T, Adams HP, Jr., Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, et al: Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864–870.
  44. Lyden P, Raman R, Liu L, Grotta J, Broderick J, Olson S, Shaw S, Spilker J, Meyer B, Emr M, Warren M, Marler J: NIHSS training and certification using a new digital video disk is reliable. Stroke 2005;36:2446–2449.
  45. Goldstein LB, Bertels C, Davis JN: Interrater reliability of the NIH stroke scale. Arch Neurol 1989;46:660–662.
  46. Kwakkel G, Veerbeek JM, van Wegen EE, Nijland R, Harmeling-van der Wel BC, Dippel DW: Predictive value of the NIHSS for ADL outcome after ischemic hemispheric stroke: does timing of early assessment matter? J Neurol Sci 2010;294:57–61.
    External Resources
  47. Di Napoli M, Papa F, Bocola V: C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001;32:917–924.
  48. Welsh P, Barber M, Langhorne P, Rumley A, Lowe GD, Stott DJ: Associations of inflammatory and haemostatic biomarkers with poor outcome in acute ischaemic stroke. Cerebrovasc Dis 2009;27:247–253.
  49. Elkind MS, Tai W, Coates K, Paik MC, Sacco RL: High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med 2006;166:2073–2080.
  50. Song IU, Kim JS, Kim YI, Lee KS, Jeong DS, Chung SW: Relationship between high-sensitivity C-reactive protein and clinical functional outcome after acute ischemic stroke in a Korean population. Cerebrovasc Dis 2009;28:545–550.
  51. Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, Dengler R, Lichtinghagen R, Weissenborn K: The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 2010;30:85–92.
  52. Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM, del Zoppo GJ, Hallenbeck JM, Rothwell NJ, Hopkins SJ, Tyrrell PJ: Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004;4:2.
  53. Urra X, Villamor N, Amaro S, Gomez-Choco M, Obach V, Oleaga L, Planas AM, Chamorro A: Monocyte subtypes predict clinical course and prognosis in human stroke. J Cereb Blood Flow Metab 2009;29:994–1002.
  54. Urra X, Cervera A, Obach V, Climent N, Planas AM, Chamorro A: Monocytes are major players in the prognosis and risk of infection after acute stroke. Stroke 2009;40:1262–1268.
  55. Cervera A, Planas AM, Justicia C, Urra X, Jensenius JC, Torres F, Lozano F, Chamorro A: Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One 2010;5:e8433.
    External Resources
  56. Worthmann H, Kempf T, Widera C, Tryc AB, Goldbecker A, Ma YT, Deb M, Tountopoulou A, Lambrecht J, Heeren M, Lichtinghagen R, Wollert KC, Weissenborn K: Growth differentiation factor 15 plasma levels and outcome after ischemic stroke. Cerebrovasc Dis 2011;32:72–78.
  57. 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.
  58. Urwyler SA, Schuetz P, Fluri F, Morgenthaler NG, Zweifel C, Bergmann A, Bingisser R, Kappos L, Steck A, Engelter S, Muller B, Christ-Crain M, Katan M: Prognostic value of copeptin: one-year outcome in patients with acute stroke. Stroke 2010;41:1564–1567.
  59. Katan M, Fluri F, Schuetz P, Morgenthaler NG, Zweifel C, Bingisser R, Kappos L, Steck A, Engelter ST, Muller B, Christ-Crain M: Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke. J Am Coll Cardiol 2010;56:1045–1053.
  60. Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, Sandercock P, Wardlaw J, Dennis M, Sudlow C: Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med 2009;6:e1000145.
    External Resources
  61. Whiteley W, Wardlaw J, Dennis M, Lowe G, Rumley A, Sattar N, Welsh P, Green A, Andrews M, Sandercock P: The use of blood biomarkers to predict poor outcome after acute transient ischemic attack or ischemic stroke. Stroke 2012;43:86–91.
  62. Giacomini M, Cook D, DeJean D, Shaw R, Gedge E: Decision tools for life support: a review and policy analysis. Crit Care Med 2006;34:864–870.
  63. Gedge E, Giacomini M, Cook D: Withholding and withdrawing life support in critical care settings: ethical issues concerning consent. J Med Ethics 2007;33:215–218.
  64. Ferrand E, Robert R, Ingrand P, Lemaire F: Withholding and withdrawal of life support in intensive-care units in France: a prospective survey. French LATAREA Group. Lancet 2001;357:9–14.
  65. Prendergast TJ, Claessens MT, Luce JM: A national survey of end-of-life care for critically ill patients. Am J Respir Crit Care Med. 1998;158:1163–1167.
  66. Wunsch H, Harrison DA, Harvey S, Rowan K: End-of-life decisions: a cohort study of the withdrawal of all active treatment in intensive care units in the United Kingdom. Intensive Care Med 2005;31:823–831.
    External Resources
  67. Varelas PN, Abdelhak T, Hacein-Bey L: Withdrawal of life-sustaining therapies and brain death in the intensive care unit. Semin Neurol 2008;28:726–735.
    External Resources
  68. Sprung CL, Cohen SL, Sjokvist P, Baras M, Bulow HH, Hovilehto S, Ledoux D, Lippert A, Maia P, Phelan D, Schobersberger W, Wennberg E, Woodcock T: End-of-life practices in European intensive care units: the Ethicus Study. JAMA 2003;290:790–797.
    External Resources
  69. Cook D, Rocker G, Marshall J, Sjokvist P, Dodek P, Griffith L, Freitag A, Varon J, Bradley C, Levy M, Finfer S, Hamielec C, McMullin J, Weaver B, Walter S, Guyatt G: Withdrawal of mechanical ventilation in anticipation of death in the intensive care unit. N Engl J Med 2003;349:1123–1132.
  70. Smedira NG, Evans BH, Grais LS, Cohen NH, Lo B, Cooke M, Schecter WP, Fink C, Epstein-Jaffe E, May C, et al: Withholding and withdrawal of life support from the critically ill. N Engl J Med 1990;322:309–315.
  71. Wood GG, Martin E: Withholding and withdrawing life-sustaining therapy in a Canadian intensive care unit. Can J Anaesth 1995;42:186–191.
  72. Prendergast TJ, Puntillo KA: Withdrawal of life support: intensive caring at the end of life. JAMA 2002;288:2732–2740.
  73. Sinuff T, Adhikari NK, Cook DJ, Schunemann HJ, Griffith LE, Rocker G, Walter SD: Mortality predictions in the intensive care unit: comparing physicians with scoring systems. Crit Care Med 2006;34:878–885.
    External Resources
  74. Worthmann H, Tryc AB, Deb M, Goldbecker A, Ma YT, Tountopoulou A, Lichtinghagen R, Weissenborn K: Linking infection and inflammation in acute ischemic stroke. Ann NY Acad Sci 2010;1207:116–122.
  75. Zandbergen EG, Hijdra A, Koelman JH, Hart AA, Vos PE, Verbeek MM, de Haan RJ: Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 2006;66:62–68.
  76. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S: Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–210.
  77. Steffen IG, Hasper D, Ploner CJ, Schefold JC, Dietz E, Martens F, Nee J, Krueger A, Jorres A, Storm C: Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients. Crit Care 2010;14:R69.
    External Resources
  78. Fugate JE, Wijdicks EF, Mandrekar J, Claassen DO, Manno EM, White RD, Bell MR, Rabinstein AA: Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann Neurol 2010;68:907–914.
    External Resources
  79. Chamorro A, Horcajada JP, Obach V, Vargas M, Revilla M, Torres F, Cervera A, Planas AM, Mensa J: The Early Systemic Prophylaxis of Infection After Stroke study: a randomized clinical trial. Stroke 2005;36:1495–1500.
  80. Schwarz S, Al-Shajlawi F, Sick C, Meairs S, Hennerici MG: Effects of prophylactic antibiotic therapy with mezlocillin plus sulbactam on the incidence and height of fever after severe acute ischemic stroke: the Mannheim infection in stroke study (MISS). Stroke 2008;39:1220–1227.
  81. Nederkoorn PJ, Westendorp WF, Hooijenga IJ, de Haan RJ, Dippel DW, Vermeij FH, Dijkgraaf MG, Prins JM, Spanjaard L, van de Beek D: Preventive antibiotics in stroke study: rationale and protocol for a randomised trial. Int J Stroke 2011;6:159–163.
    External Resources
  82. Liesz A, Hagmann S, Zschoche C, Adamek J, Zhou W, Sun L, Hug A, Zorn M, Dalpke A, Nawroth P, Veltkamp R: The spectrum of systemic immune alterations after murine focal ischemia: immunodepression versus immunomodulation. Stroke 2009;40:2849–2858.
  83. Klehmet J, Harms H, Richter M, Prass K, Volk HD, Dirnagl U, Meisel A, Meisel C: Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience 2009;158:1184–1193.
  84. Zhang DP, Yan FL, Xu HQ, Zhu YX, Yin Y, Lu HQ: A decrease of human leucocyte antigen-DR expression on monocytes in peripheral blood predicts stroke-associated infection in critically-ill patients with acute stroke. Eur J Neurol 2009;16:498–505.

Author Contacts

Andreas Meisel

Department of Neurology, Charité – Universitätsmedizin Berlin

Charitéplatz 1

DE–10117 Berlin (Germany)

Tel. +49 30 450 560 026, E-Mail andreas.meisel@charite.de


Article / Publication Details

First-Page Preview
Abstract of Translational Research in Stroke

Received: January 16, 2012
Accepted: March 16, 2012
Published online: June 15, 2012
Issue release date: June 2012

Number of Print Pages: 9
Number of Figures: 4
Number of Tables: 2

ISSN: 1015-9770 (Print)
eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Mathers CD, Boerma T, Ma Fat D: Global and regional causes of death. Br Med Bull 2009;92:7–32.
    External Resources
  2. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U: Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 2005;6:775–786.
  3. Koennecke HC, Belz W, Berfelde D, Endres M, Fitzek S, Hamilton F, Kreitsch P, Mackert BM, Nabavi DG, Nolte CH, Pohls W, Schmehl I, Schmitz B, von Brevern M, Walter G, Heuschmann PU: Factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit. Neurology 2011;77:965–972.
    External Resources
  4. Hilker R, Poetter C, Findeisen N, Sobesky J, Jacobs A, Neveling M, Heiss WD: Nosocomial pneumonia after acute stroke: implications for neurological intensive care medicine. Stroke 2003;34:975–981.
  5. Langhorne P, Stott DJ, Robertson L, MacDonald J, Jones L, McAlpine C, Dick F, Taylor GS, Murray G: Medical complications after stroke: a multicenter study. Stroke 2000;31:1223–1229.
  6. Katzan IL, Cebul RD, Husak SH, Dawson NV, Baker DW: The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology 2003;60:620–625.
  7. Aslanyan S, Weir CJ, Diener HC, Kaste M, Lees KR: Pneumonia and urinary tract infection after acute ischaemic stroke: a tertiary analysis of the GAIN International trial. Eur J Neurol 2004;11:49–53.
  8. 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;15:1324–1331.
  9. Wartenberg KE, Stoll A, Funk A, Meyer A, Schmidt JM, Berrouschot J: Infection after acute ischemic stroke: risk factors, biomarkers, and outcome. Stroke Res Treat 2011;2011:830614.
    External Resources
  10. Kumar S, Selim MH, Caplan LR: Medical complications after stroke. Lancet Neurol 2010;9:105–118.
  11. Polderman KH: Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955–1969.
    External Resources
  12. van der Worp HB, Macleod MR, Kollmar R: Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab 2010;30:1079–1093.
  13. Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD: Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 2010;41:2265–2270.
  14. Meisel A: Effective fever control in acute stroke: still wanted! Cerebrovasc Dis 2011;31:390–391.
  15. Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U, Volk HD, Meisel A: 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;198:725–736.
  16. Meisel C, Prass K, Braun J, Victorov I, Wolf T, Megow D, Halle E, Volk HD, Dirnagl U, Meisel A: Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke. Stroke 2004;35:2–6.
  17. Westendorp WF, Vermeij JD, Vermeij F, Den Hertog HM, Dippel DW, van de Beek D, Nederkoorn PJ: Antibiotic therapy for preventing infections in patients with acute stroke. Cochrane Database Syst Rev 2012;1:CD008530.
  18. Feuerstein GZ, Chavez J: Translational medicine for stroke drug discovery: the pharmaceutical industry perspective. Stroke 2009;40(3 Suppl):S121–125.
    External Resources
  19. Bruno A, Biller J, Adams HP, Jr., Clarke WR, Woolson RF, Williams LS, Hansen MD: Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology 1999;52:280–284.
  20. Hajat C, Hajat S, Sharma P: Effects of poststroke pyrexia on stroke outcome: a meta-analysis of studies in patients. Stroke 2000;31:410–414.
  21. Nuutinen J, Liu Y, Laakso MP, Karonen JO, Roivainen R, Vanninen RL, Partanen K, Ostergaard L, Sivenius J, Aronen HJ: Assessing the outcome of stroke: a comparison between MRI and clinical stroke scales. Acta Neurol Scand 2006;113:100–107.
  22. Whiteley W, Chong WL, Sengupta A, Sandercock P: Blood markers for the prognosis of ischemic stroke: a systematic review. Stroke 2009;40:e380–e389.
  23. Ahmad O, Wardlaw J, Whiteley WN: Correlation of levels of neuronal and glial markers with radiological measures of infarct volume in ischaemic stroke: a systematic review. Cerebrovasc Dis 2012;33:47–54.
  24. Hasan N, McColgan P, Bentley P, Edwards RJ, Sharma P: Towards the identification of blood biomarkers for acute stroke in humans: a comprehensive systematic review. Br J Clin Pharmacol 2012, E-pub ahead of print.
  25. Nakajoh K, Nakagawa T, Sekizawa K, Matsui T, Arai H, Sasaki H: Relation between incidence of pneumonia and protective reflexes in post-stroke patients with oral or tube feeding. J Intern Med 2000;247:39–42.
  26. 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(suppl 2):770–773.
    External Resources
  27. Chamorro A, Urra X, Planas AM: Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke 2007;38:1097–1103.
  28. Emsley HC, Hopkins SJ: Acute ischaemic stroke and infection: recent and emerging concepts. Lancet Neurol 2008;7:341–353.
  29. Dziedzic T, Slowik A, Szczudlik A: Nosocomial infections and immunity: lesson from brain-injured patients. Crit Care 2004;8:266–270.
    External Resources
  30. Wong CH, Jenne CN, Lee WY, Leger C, Kubes P: Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 2011;334:101–105.
  31. Harms H, Prass K, Meisel C, Klehmet J, Rogge W, Drenckhahn C, Gohler J, Bereswill S, Gobel U, Wernecke KD, Wolf T, Arnold G, Halle E, Volk HD, Dirnagl U, Meisel A: Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One 2008;3:e2158.
  32. Haeusler KG, Schmidt WU, Fohring F, Meisel C, Helms T, Jungehulsing GJ, Nolte CH, Schmolke K, Wegner B, Meisel A, Dirnagl U, Villringer A, Volk HD: Cellular immunodepression preceding infectious complications after acute ischemic stroke in humans. Cerebrovasc Dis 2008;25:50–58.
  33. Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Torres F, Planas AM: Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke. J Neurol Neurosurg Psychiatry 2006;77:1279–1281.
  34. Czlonkowska A, Ryglewicz D, Lechowicz W: Basic analytical parameters as the predictive factors for 30-day case fatality rate in stroke. Acta Neurol Scand 1997;95:121–124.
  35. Vogelgesang A, Grunwald U, Langner S, Jack R, Broker BM, Kessler C, Dressel A: Analysis of lymphocyte subsets in patients with stroke and their influence on infection after stroke. Stroke 2008;39:237–241.
  36. Woiciechowsky C, Asadullah K, Nestler D, Eberhardt B, Platzer C, Schoning B, Glockner F, Lanksch WR, Volk HD, Docke WD: Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 1998;4:808–813.
  37. Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Gomez-Choco M, Torres F, Planas AM: Catecholamines, infection, and death in acute ischemic stroke. J Neurol Sci 2007;252:29–35.
  38. Prass K, Braun JS, Dirnagl U, Meisel C, Meisel A: Stroke propagates bacterial aspiration to pneumonia in a model of cerebral ischemia. Stroke 2006;37:2607–2612.
  39. Harms H, Reimnitz P, Bohner G, Werich T, Klingebiel R, Meisel C, Meisel A: Influence of stroke localization on autonomic activation, immunodepression, and post-stroke infection. Cerebrovasc Dis 2011;32:552–560.
  40. Meisel C, Meisel A: Suppressing immunosuppression after stroke. N Engl J Med 2011;365:2134–2136.
  41. Schabitz WR, Kruger C, Pitzer C, Weber D, Laage R, Gassler N, Aronowski J, Mier W, Kirsch F, Dittgen T, Bach A, Sommer C, Schneider A: A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF). J Cereb Blood Flow Metab 2008;28:29–43.
    External Resources
  42. Schabitz WR, Laage R, Vogt G, Koch W, Kollmar R, Schwab S, Schneider D, Hamann GF, Rosenkranz M, Veltkamp R, Fiebach JB, Hacke W, Grotta JC, Fisher M, Schneider A: AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 2010;41:2545–2551.
    External Resources
  43. Brott T, Adams HP, Jr., Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, et al: Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864–870.
  44. Lyden P, Raman R, Liu L, Grotta J, Broderick J, Olson S, Shaw S, Spilker J, Meyer B, Emr M, Warren M, Marler J: NIHSS training and certification using a new digital video disk is reliable. Stroke 2005;36:2446–2449.
  45. Goldstein LB, Bertels C, Davis JN: Interrater reliability of the NIH stroke scale. Arch Neurol 1989;46:660–662.
  46. Kwakkel G, Veerbeek JM, van Wegen EE, Nijland R, Harmeling-van der Wel BC, Dippel DW: Predictive value of the NIHSS for ADL outcome after ischemic hemispheric stroke: does timing of early assessment matter? J Neurol Sci 2010;294:57–61.
    External Resources
  47. Di Napoli M, Papa F, Bocola V: C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001;32:917–924.
  48. Welsh P, Barber M, Langhorne P, Rumley A, Lowe GD, Stott DJ: Associations of inflammatory and haemostatic biomarkers with poor outcome in acute ischaemic stroke. Cerebrovasc Dis 2009;27:247–253.
  49. Elkind MS, Tai W, Coates K, Paik MC, Sacco RL: High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med 2006;166:2073–2080.
  50. Song IU, Kim JS, Kim YI, Lee KS, Jeong DS, Chung SW: Relationship between high-sensitivity C-reactive protein and clinical functional outcome after acute ischemic stroke in a Korean population. Cerebrovasc Dis 2009;28:545–550.
  51. Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, Dengler R, Lichtinghagen R, Weissenborn K: The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 2010;30:85–92.
  52. Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM, del Zoppo GJ, Hallenbeck JM, Rothwell NJ, Hopkins SJ, Tyrrell PJ: Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004;4:2.
  53. Urra X, Villamor N, Amaro S, Gomez-Choco M, Obach V, Oleaga L, Planas AM, Chamorro A: Monocyte subtypes predict clinical course and prognosis in human stroke. J Cereb Blood Flow Metab 2009;29:994–1002.
  54. Urra X, Cervera A, Obach V, Climent N, Planas AM, Chamorro A: Monocytes are major players in the prognosis and risk of infection after acute stroke. Stroke 2009;40:1262–1268.
  55. Cervera A, Planas AM, Justicia C, Urra X, Jensenius JC, Torres F, Lozano F, Chamorro A: Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One 2010;5:e8433.
    External Resources
  56. Worthmann H, Kempf T, Widera C, Tryc AB, Goldbecker A, Ma YT, Deb M, Tountopoulou A, Lambrecht J, Heeren M, Lichtinghagen R, Wollert KC, Weissenborn K: Growth differentiation factor 15 plasma levels and outcome after ischemic stroke. Cerebrovasc Dis 2011;32:72–78.
  57. 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.
  58. Urwyler SA, Schuetz P, Fluri F, Morgenthaler NG, Zweifel C, Bergmann A, Bingisser R, Kappos L, Steck A, Engelter S, Muller B, Christ-Crain M, Katan M: Prognostic value of copeptin: one-year outcome in patients with acute stroke. Stroke 2010;41:1564–1567.
  59. Katan M, Fluri F, Schuetz P, Morgenthaler NG, Zweifel C, Bingisser R, Kappos L, Steck A, Engelter ST, Muller B, Christ-Crain M: Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke. J Am Coll Cardiol 2010;56:1045–1053.
  60. Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, Sandercock P, Wardlaw J, Dennis M, Sudlow C: Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med 2009;6:e1000145.
    External Resources
  61. Whiteley W, Wardlaw J, Dennis M, Lowe G, Rumley A, Sattar N, Welsh P, Green A, Andrews M, Sandercock P: The use of blood biomarkers to predict poor outcome after acute transient ischemic attack or ischemic stroke. Stroke 2012;43:86–91.
  62. Giacomini M, Cook D, DeJean D, Shaw R, Gedge E: Decision tools for life support: a review and policy analysis. Crit Care Med 2006;34:864–870.
  63. Gedge E, Giacomini M, Cook D: Withholding and withdrawing life support in critical care settings: ethical issues concerning consent. J Med Ethics 2007;33:215–218.
  64. Ferrand E, Robert R, Ingrand P, Lemaire F: Withholding and withdrawal of life support in intensive-care units in France: a prospective survey. French LATAREA Group. Lancet 2001;357:9–14.
  65. Prendergast TJ, Claessens MT, Luce JM: A national survey of end-of-life care for critically ill patients. Am J Respir Crit Care Med. 1998;158:1163–1167.
  66. Wunsch H, Harrison DA, Harvey S, Rowan K: End-of-life decisions: a cohort study of the withdrawal of all active treatment in intensive care units in the United Kingdom. Intensive Care Med 2005;31:823–831.
    External Resources
  67. Varelas PN, Abdelhak T, Hacein-Bey L: Withdrawal of life-sustaining therapies and brain death in the intensive care unit. Semin Neurol 2008;28:726–735.
    External Resources
  68. Sprung CL, Cohen SL, Sjokvist P, Baras M, Bulow HH, Hovilehto S, Ledoux D, Lippert A, Maia P, Phelan D, Schobersberger W, Wennberg E, Woodcock T: End-of-life practices in European intensive care units: the Ethicus Study. JAMA 2003;290:790–797.
    External Resources
  69. Cook D, Rocker G, Marshall J, Sjokvist P, Dodek P, Griffith L, Freitag A, Varon J, Bradley C, Levy M, Finfer S, Hamielec C, McMullin J, Weaver B, Walter S, Guyatt G: Withdrawal of mechanical ventilation in anticipation of death in the intensive care unit. N Engl J Med 2003;349:1123–1132.
  70. Smedira NG, Evans BH, Grais LS, Cohen NH, Lo B, Cooke M, Schecter WP, Fink C, Epstein-Jaffe E, May C, et al: Withholding and withdrawal of life support from the critically ill. N Engl J Med 1990;322:309–315.
  71. Wood GG, Martin E: Withholding and withdrawing life-sustaining therapy in a Canadian intensive care unit. Can J Anaesth 1995;42:186–191.
  72. Prendergast TJ, Puntillo KA: Withdrawal of life support: intensive caring at the end of life. JAMA 2002;288:2732–2740.
  73. Sinuff T, Adhikari NK, Cook DJ, Schunemann HJ, Griffith LE, Rocker G, Walter SD: Mortality predictions in the intensive care unit: comparing physicians with scoring systems. Crit Care Med 2006;34:878–885.
    External Resources
  74. Worthmann H, Tryc AB, Deb M, Goldbecker A, Ma YT, Tountopoulou A, Lichtinghagen R, Weissenborn K: Linking infection and inflammation in acute ischemic stroke. Ann NY Acad Sci 2010;1207:116–122.
  75. Zandbergen EG, Hijdra A, Koelman JH, Hart AA, Vos PE, Verbeek MM, de Haan RJ: Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 2006;66:62–68.
  76. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S: Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–210.
  77. Steffen IG, Hasper D, Ploner CJ, Schefold JC, Dietz E, Martens F, Nee J, Krueger A, Jorres A, Storm C: Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients. Crit Care 2010;14:R69.
    External Resources
  78. Fugate JE, Wijdicks EF, Mandrekar J, Claassen DO, Manno EM, White RD, Bell MR, Rabinstein AA: Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann Neurol 2010;68:907–914.
    External Resources
  79. Chamorro A, Horcajada JP, Obach V, Vargas M, Revilla M, Torres F, Cervera A, Planas AM, Mensa J: The Early Systemic Prophylaxis of Infection After Stroke study: a randomized clinical trial. Stroke 2005;36:1495–1500.
  80. Schwarz S, Al-Shajlawi F, Sick C, Meairs S, Hennerici MG: Effects of prophylactic antibiotic therapy with mezlocillin plus sulbactam on the incidence and height of fever after severe acute ischemic stroke: the Mannheim infection in stroke study (MISS). Stroke 2008;39:1220–1227.
  81. Nederkoorn PJ, Westendorp WF, Hooijenga IJ, de Haan RJ, Dippel DW, Vermeij FH, Dijkgraaf MG, Prins JM, Spanjaard L, van de Beek D: Preventive antibiotics in stroke study: rationale and protocol for a randomised trial. Int J Stroke 2011;6:159–163.
    External Resources
  82. Liesz A, Hagmann S, Zschoche C, Adamek J, Zhou W, Sun L, Hug A, Zorn M, Dalpke A, Nawroth P, Veltkamp R: The spectrum of systemic immune alterations after murine focal ischemia: immunodepression versus immunomodulation. Stroke 2009;40:2849–2858.
  83. Klehmet J, Harms H, Richter M, Prass K, Volk HD, Dirnagl U, Meisel A, Meisel C: Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience 2009;158:1184–1193.
  84. Zhang DP, Yan FL, Xu HQ, Zhu YX, Yin Y, Lu HQ: A decrease of human leucocyte antigen-DR expression on monocytes in peripheral blood predicts stroke-associated infection in critically-ill patients with acute stroke. Eur J Neurol 2009;16:498–505.