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Methylene blue administration during cardio-pulmonary resuscitation and early reperfusion protects against cortical blood-brain barrier disruption
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. (cardiopulmonary resuscitation)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

Objective: The present study was designed to study the effects of cardiac arrest and cardiopulmonary resuscitation (CPR) on blood-brain barrier (BBB) permeability and subsequent neurological injury. It also tests the cerebral effects of MB on the maintenance of BBB integrity, the production of nitric oxide (NO) and regulation of nitric oxide synthases (NOS) in cerebral cortex.

Intervention: The control group (CA, n=16) underwent 12 min cardiac arrest without subsequent CPR, after which the brain of the animals was removed immediately or after 15 and 30 min. The other two groups with 12 min cardiac arrest and subsequent 8 min CPR received either an infusion of saline (CA-MB group, n=10) or an infusion of saline with MB (CA+MB, n= 12) started one minute after the start of CPR and continued 50 min after return of spontaneous circulation (ROSC).  In both the latter (CA-MB and CA+MB) groups the brains were removed for histological analysis at the following time points: 30, 60, 180 min after ROSC.

Main Results: In all the groups an increase of necrotic neurons and albumin immunoreactivity was demonstrated with increasing duration of ischemia and reperfusion time. The immunohistochemistry analysis indicated less blood brain barrier disruption in the animals receiving MB (CA+MB group) evidenced by decreased albumin leakage (P<0.01), water content (P=0.02), potassium (P=0.04), but also decreased neuronal injury (P<0.001) in this group in comparison with the group that was not treated with MB (CA-MB). Similarly, MB treatment reduced nitrite/nitrate ratio (P=0.02), iNOS expression (P<0.01), nNOS expression (P<0.01).

Conclusion: Cerebral edema, increase BBB permeability and neurologic injury are observed early in ischemia induced by cardiac arrest. MB markedly reduced BBB disruption and subsequent neurologic injury. These cerebral cortical effects after the exposure to MB appear to be associated with a decrease of NO measured by nitrate/nitrite and different effects on NOS.

Keywords [en]
Methylene blue, blood brain barrier, cardiopulmonary resuscitation, cardiac arrest, nitric oxide, nitric oxide synthases
National Category
Anesthesiology and Intensive Care Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-106805OAI: oai:DiVA.org:uu-106805DiVA, id: diva2:226776
Available from: 2009-07-06 Created: 2009-07-04 Last updated: 2015-06-09Bibliographically approved
In thesis
1. Cerebral Protection in Experimental Cardiopulmonary Resuscitation: With Special Reference to the Effects of Methylene Blue
Open this publication in new window or tab >>Cerebral Protection in Experimental Cardiopulmonary Resuscitation: With Special Reference to the Effects of Methylene Blue
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Although survival rates are increasing, brain injury continues to be a leading cause of death after cardiac arrest (CA). Permanent brain damage after CA is determined by limited tolerance to ischemia from CA and cardiopulmonary resuscitation (CPR), as well as the unique cerebral response to reperfusion after return of spontaneous circulation (ROSC). A major pathway leading to neurotoxic cascade and neuronal injury after CA involves the increased presence of reactive oxygen and nitrogen species generated during ischemia and reperfusion. The magnitude of cerebral oxidative injury induced by free radicals increased with the duration of CA (Paper I). Nitric oxide (NO), a free radical responsible for the formation of reactive nitrogen species, is increased during global ischemia from CA and reperfusion (Paper IV). Hypothetically, the administration of a drug that counteracts the overproduction of NO and also acts as a scavenger of oxygen free radicals might be warranted in order to reduce the damage caused by nitrosative and oxidative stress. For these purposes we used methylene blue (MB), an old dye that has been used in medicine for almost half a century, and an experimental pig model of 20 min of ventricular fibrillation (VF) to reflect a clinical scenario of ischemia/reperfusion injury. Administration of MB added to a hypertonic-hyperoncotic solution (MBHSD) that was started during CPR and continued for 50 min after ROSC increased short-term survival by decreasing myocardial damage, as well as cerebral peroxidation and inflammatory injury (Paper II). Immunostaining of cerebral tissue collected at different time points after CA and ROSC (Paper IV) provided experimental evidence that cortical blood-brain barrier (BBB) disruption begins as early as  during the initial phase of untreated as well as treated CA. The results indicated that MB administration reduced the neurologic injury and BBB disruption considerably, but did not reverse the ongoing detrimental processes. The demonstrated positive effects of MB were related to a decrease of nitrite/nitrate tissue content, and thus to a decrease of excess NO due to the MB inhibitory effects on NOS isoforms. A mixture of MB in hypertonic sodium lactate (MBL) was investigated to facilitate administration of MB in “the field.” Based on findings that MBL cardio- and neuroprotective properties were similar to those of MBHSD, there is reason to believe that the use of MBL might be extended during ongoing CPR and after ROSC (Paper III). It would therefore make sense to try using MB as a pharmacological neuroprotectant during or after clinical CPR in order to expand the temporal therapeutic window before other measures for neuroprotection such as hypothermia are available.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. p. 79
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 466
Keywords
Cardiac arrest, cardiopulmonary resuscitation, reperfusion injury, methylene blue, nitric oxide, nitric oxide synthases, blood-brain barrier
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology
Identifiers
urn:nbn:se:uu:diva-106831 (URN)978-91-554-7566-6 (ISBN)
Public defence
2009-09-11, Hedstrandsalen, Akademiska Sjukhuset, entrance no. 70, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-08-20 Created: 2009-07-06 Last updated: 2010-05-28Bibliographically approved

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Miclescu, AdrianaSharma, Hari ShankerMartijn, CécileWiklund, Lars

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