Nature Has No Principle-Inflammation Following Brain Injury Is Neither Good Nor Evil* Andrea Kleindienst, MD, PhD Michael Buchfelder, MD, PhD Sebastian Brandner, MD Department of Neurosurgery Friedrich-Alexander-University Erlangen-Nurnberg Erlangen, Germany

oth traumatic brain injury (TBI) and ischemic/hemorrhagic stroke render a substantial burden of mor­ bidity and mortality to the society. While around 1.4 million persons suffer from TBI each year, causing about 50,000 deaths from TBI-related injuries, almost a million adults are affected by stroke annually, with around 150,000 related deaths per year in the United States (1). Thus, acute brain injury resulting from either the mechanical type of TBI or the ischemic or hemorrhagic type of stroke represents an enormous challenge requiring continuing improvement of therapeutic approaches. Research over the past decades has elucidated the patho­ physiology of neurotrauma after brain injury. Beside the “primary” damage, numerous “secondary” events evolve after­ ward, including activation of neuroinflammatory cascades, toxic neurotransmitter release, or production of free radicals, which have a crucial impact on the subsequent neurological damage and the final outcome (2, 3). Current management protocols have established the importance of maintaining adequate physiological variables, that is, cerebral perfusion and oxygenation and avoiding subsequent complications (2, 4) and thereby bisected the mortality following brain injury. However, any neuroprotective strategy—as promising in the experimental setting—including the inhibition of inflamma­ tory cascades or of the generation of free radicals, has failed in clinical studies (5,6). One lesson we learned over the past decades of brain research is that nothing is exactly as it appears to be. The French poet and Nobel Prize laureate Anatole France coined

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'See also p. 1910. Key Words: brain injury; complement system; inflammation; lectin pathway; neuroprotection; neuroregeneration Dr. Kleindienst is employed by Klinikum Amberg, University of Erlangen, and received grant support from Otzuka Pharma. Dr. Buchfelder served as board member for Acrostudy Pfizer and lectured for Pfizer, Novartis, Ipsen, and Novo Nordisk. His institution received grant support from Pfizer (AcroStudy Central MR Reading and Experiential studies) and Novartis (Pituitary Surgery Courses and Clinical Studies). Dr. Brandner has dis­ closed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000479 1958

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the phrase “Nature has no principles. She makes no distinction between good and evil.” This is especially true for inflamma­ tion and has to be kept in mind interpreting the results of Stocchetti’s group. As much as the attenuation of the inflammatory response may be neuroprotective as many reports focus on the participation of inflammation in neuroregeneration (7). In this issue of Critical Care Medicine, Longhi et al (8) continue their previous work on the role of inflammation in neurotrauma by altering the lectin complement pathway, a cascade reaction similar to the classical complement pathway. Specifically, they exposed mice to an experimental brain injury (controlled cortical impact, CCI) and quantified the functional outcome and histological findings. They compared mice with an intact complement system (wild-type [WT] mice) and mice with a blocked lectin pathway (mannose-binding lectin [MBL]—an activator of the lectin pathway—knockout mice, MBL-/-). In contrast to a previous report about an increased acute hippocampal cell death 6 hours after mild TBI in MBL/ - mice (9), Longhi et al (8) found an attenuated cortical cell loss in MBL-/- mice when compared with WT mice at 5 weeks after CCI. Furthermore, the authors demonstrated a signifi­ cant functional improvement in M BL-/- mice as assessed by a neuroscore and beam walking test beginning at 2 weeks and continuing up to 4 weeks postinjury. One explanation of the discrepancy of both studies may be the severity of the brain injury. However, further studies are warranted in order to con­ firm or exclude a neuroprotective effect of MBL modulation. Translating their experimental findings into the clinical set­ ting, Longhi et al (8) evaluated the MBL expression in tissue samples from six patients who underwent surgery for a cere­ bral contusion at 6 hours to 5 days after TBI. They describe for the first time MBL deposition in the human brain after TBI and demonstrate a similar pattern of MBL distribution within the brain of patients as they found after experimental brain injury in the mouse model. Consequently, the results of the clinical and experimental studies of Longhi et al (8) published in this issue of Critical Care Medicine support the view of a beneficial role of modu­ lating inflammation by blocking the lectin pathway after brain injury. This conception is in line with previous reports about more favorable outcomes of individuals with genetic MBL deficiency after stroke or myocardial infarction (10, 11). The exact mechanisms of the absence of MBL have to be elucidated further, that is, whether it conveys a neuroprotective, a neuroregenerative, or an attenuated neurodegenerative potential. Longhi et al (8) found no association between MBL defi­ ciency and complement activation in their mouse model as demonstrated by a similar increase of plasma C3 fragments both in WT and M BL-/- mice. Hence, the classical comple­ ment pathway seems not to be affected by a MBL modulation August 2014 • Volume 42 • Number 8

Editorials

and does not participate to the effects observed in the pres­ ent study. Unfortunately, the article lacks a sound physiologi­ cal explanation for the potentially harmful effects of MBL or rather for the protective mechanisms of its deficiency. Some suggestions about potential mechanisms involving a direct action of MBL on cerebral or endothelial cells remain vague. In summary, the presented data give rise to the hope that a specific modulation of neuroinflammation could eventually be a therapeutic approach in neurotrauma, and either the lectin pathway in general or MBL specifically might be a potential target, although the underlying pathophysiological mecha­ nisms might still remain to be elucidated.

REFERENCES 1. Stead LG, Bodhit AN, Patel PS, et al; Emergency Medicine Traumatic Brain Injury Research Network Investigators: TBI surveillance using the common data elements for traumatic brain injury: A population study. Int J Emerg M ed 2013; 6:5 2. Carney NA, Ghajar J: Guidelines for the management of severe traumatic brain injury. Introduction. J Neurotrauma 2007; 24(Suppl 1 ):S 1-S 2 3. Adams HP Jr, del Zoppo G, Alberts MJ, et al; American Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care O utcom es in Research Interdisciplinary Working G roups: Guidelines for the early management of adults with isch­ emic stroke: A guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology

Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care O utcomes in Research Interdisciplinary W orking Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007; 3 8 :1 6 5 5 -1 7 1 1 4. Bratton SL, Chestnut RM, Ghajar J, et al: Guidelines for the manage­ ment of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma 2007; 24(Suppl 1 ):S 3 7-S 4 4 5. Bratton SL, Chestnut RM, Ghajar J, et al: Guidelines for the manage­ ment of severe traumatic brain injury. XV. Steroids. J Neurotrauma 2007; 24(Suppl 1 ):S 91-S 95 6. Weinberger JM: Evolving therapeutic approaches to treating acute ischemic stroke. J Neurol S ci 2006; 2 4 9 :1 0 1 -1 0 9 7. Kirkham M, Berg DA, Simon A: Microglia activation during neu­ roregeneration in the adult vertebrate brain. Neurosci Lett 2011; 4 9 7 :1 1 -1 6 8. Longhi L, Orsini F, De Blasio D, et al: Mannose-Binding Lectin Is Expressed After Clinical and Experimental Traumatic Brain Injury and Its Deletion Is Protective. Crit Care Med 2014; 42:1910-1918 9. Yager PH, You Z, Qin T, et al: Mannose binding lectin gene deficiency increases susceptibility to traumatic brain injury in mice. J Cereb B lood Flow Metab 2008; 2 8 :1 0 3 0 -1 0 3 9 10. Cervera A, Planas AM, Justicia C, et al: Genetically-defined deficiency of mannose-binding lectin is associated with protection after experi­ mental stroke in mice and outcome in human stroke. PLoS One 2010; 5:e8433 11. Trendelenburg M, Theroux P, Stebbins A, et al: Influence of func­ tional deficiency of complement mannose-binding lectin on outcome of patients with acute ST-elevation myocardial infarction undergo­ ing primary percutaneous coronary intervention. Eur Heart J 2010; 3 1 :1 1 8 1 -1 1 8 7

Prognostication Following Cardiac Arrest: Do We Have Our Patients’ Safety in Mind?* Romergryko G. Geocadin, MD

Santosh B. Murthy, MD, MPH

Department of Neurology Department of Anesthesiology and Critical Care Medicine Department of Neurosurgery; and Department of Medicine Johns Hopkins University School of Medicine Baltimore, MD

Department of Neurology; and Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore, MD

he practice of prognostication in post cardiac arrest (PCA) patients has grave importance particularly in the era where resources are limited and cost containment is emphasized. Prior to the introduction of therapeutic hypother­ mia (TH) in comatose survivors of cardiac arrest, a clinical prac­ tice guideline advocates for 72 hours postarrest as an acceptable time cutoff for prognostication of neurological recovery (1). The introduction of TH shifted the paradigm as it improved out­ comes and increased attention to the postarrest care. TH has also renewed the interest in prognostication (2). Hence, developing validated prognostic tools and establishing the optimal timing and predictive accuracy of tests used in response to the changes to outcomes that TH has caused is one of the most pressing research needs in postresuscitation care (3).

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*See also p. 1919. Key Words: cardiac arrest; patient safety; prognostication; therapeutic hypothermia Dr. Geocadin is supported, in part, by 5R 01H L071568 and RO I NS074425. Dr. Geocadin provided expert testimony as Medicolegal Con­ sult, received grant support from the National Institutes of Health (NIH), and received support for article research from the NIH. Dr. Murthy has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/C C M .0000000000000394

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Nature has no principle-inflammation following brain injury is neither good nor evil*.

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