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Cerebral Protection in Experimental Cardiopulmonary Resuscitation: With Special Reference to the Effects of Methylene Blue
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. (Cardiopulmonary resuscitation)
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis , 2009. , s. 79
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 466
Nyckelord [en]
Cardiac arrest, cardiopulmonary resuscitation, reperfusion injury, methylene blue, nitric oxide, nitric oxide synthases, blood-brain barrier
Nationell ämneskategori
Anestesi och intensivvård
Forskningsämne
Anestesiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-106831ISBN: 978-91-554-7566-6 (tryckt)OAI: oai:DiVA.org:uu-106831DiVA, id: diva2:226809
Disputation
2009-09-11, Hedstrandsalen, Akademiska Sjukhuset, entrance no. 70, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-08-20 Skapad: 2009-07-06 Senast uppdaterad: 2010-05-28Bibliografiskt granskad
Delarbeten
1. Evidence for Time-dependent Maximum Increase ofFree Radical Damage and Eicosanoid Formation in theBrain as Related to Duration of Cardiac Arrest andCardio-pulmonary Resuscitation
Öppna denna publikation i ny flik eller fönster >>Evidence for Time-dependent Maximum Increase ofFree Radical Damage and Eicosanoid Formation in theBrain as Related to Duration of Cardiac Arrest andCardio-pulmonary Resuscitation
Visa övriga...
2003 (Engelska)Ingår i: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 37, nr 3, s. 251-256Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Recovery of neurological function in patients following cardiac arrest and cardiopulmonary resuscitation (CPR) is a complex event. Free radical induced oxidative stress is supposed to be involved in this process. We studied levels of 8-iso-PGF2alpha (indicating oxidative injury) and 15-keto-dihydro-PGF2alpha (indicating inflammatory response) in venous plasma obtained from the jugular bulb in a porcine model of experimental cardiopulmonary resuscitation (CPR) where 2, 5, 8, 10 or 12 min of ventricular fibrillation (VF) was followed by 5 or 8 min of closed-chest CPR. A significant increase of 8-iso-PGF2alpha was observed immediately following restoration of spontaneous circulation in all experiments of various duration of VF and CPR. No such increase was seen in a control group. When compared between the groups there was a duration-dependent maximum increase of 8-iso-PGF2alpha which was greatest in animals subjected to the longest period (VF12 min + CPR8 min) of no or low blood flow. In contrast, the greatest increase of 15-keto-dihydro-PGF2alpha was observed in the 13 min group (VF8 min + CPR5 min). Thus, a time-dependent cerebral oxidative injury occurs in conjunction which cardiac arrest and CPR.

Nyckelord
Ischemia reperfusion, Prostaglandins, Isoprostanes
Nationell ämneskategori
Anestesi och intensivvård
Identifikatorer
urn:nbn:se:uu:diva-106804 (URN)10.1080/1071576021000043058 (DOI)12688420 (PubMedID)
Tillgänglig från: 2009-07-06 Skapad: 2009-07-04 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
2. Cardio-cerebral and metabolic effects of methylene blue in hypertonic sodium lactate during experimental cardiopulmonary resuscitation
Öppna denna publikation i ny flik eller fönster >>Cardio-cerebral and metabolic effects of methylene blue in hypertonic sodium lactate during experimental cardiopulmonary resuscitation
2007 (Engelska)Ingår i: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 75, nr 1, s. 88-97Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: Methylene blue (MB) administered with a hypertonic-hyperoncotic solution reduces the myocardial and cerebral damage due to ischaemia and reperfusion injury after experimental cardiac arrest and also increases short-term survival. As MB precipitates in hypertonic sodium chloride, an alternative mixture of methylene blue in hypertonic sodium lactate (MBL) was developed and investigated during and after cardiopulmonary resuscitation (CPR). METHODS: Using an experimental pig model of cardiac arrest (12 min cardiac arrest and 8 min CPR) the cardio-cerebral and metabolic effects of MBL (n=10), MB in normal saline (MBS; n=10) or in hypertonic saline dextran (MBHSD; n=10) were compared. Haemodynamic variables and cerebral cortical blood flow (CCBF) were recorded. Biochemical markers of cerebral oxidative injury (8-iso-PGF2alpha), inflammation (15-keto-dihydro-PGF2alpha), and neuronal damage (protein S-100beta) were measured in blood from the sagittal sinus, whereas markers of myocardial injury, electrolytes, and lactate were measured in arterial plasma. RESULTS: There were no differences between groups in survival, or in biochemical markers of cerebral injury. In contrast, the MBS group exhibited not only increased CKMB (P<0.001) and troponin I in comparison with MBHSD (P=0.019) and MBL (P=0.037), but also greater pulmonary capillary wedge pressure 120 min after return of spontaneous circulation (ROSC). Lactate administration had an alkalinizing effect started 120 min after ROSC. CONCLUSIONS: Methylene blue in hypertonic sodium lactate may be used against reperfusion injury during experimental cardiac arrest, having similar effects as MB with hypertonic saline-dextran, but in addition better myocardial protection than MB with normal saline. The neuroprotective effects did not differ.

Nyckelord
Cardiopulmonary resuscitation, Dextran, Hypertonic solutions, Methylene blue, Oxidative injury, Sodium lactate
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-16049 (URN)10.1016/j.resuscitation.2007.03.014 (DOI)000250265300013 ()17482336 (PubMedID)
Tillgänglig från: 2008-05-31 Skapad: 2008-05-31 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
3. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest
Öppna denna publikation i ny flik eller fönster >>Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest
2006 (Engelska)Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 34, nr 11, s. 2806-2813Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVE: Methylene blue (MB), a free-radical scavenger inhibiting the production and actions of nitric oxide, may counteract excessive vasodilatation induced by nitric oxide during cardiac arrest. Effects of MB in cardiac arrest and cardiopulmonary resuscitation were investigated. DESIGN: Randomized, prospective, laboratory animal study. SETTING: University animal research laboratory. SUBJECTS: A total of 63 piglets of both sexes. INTERVENTIONS: A pig model of extended cardiac arrest (12 mins of untreated cardiac arrest and 8 mins of cardiopulmonary resuscitation) was employed to assess the addition or no addition of MB to a hypertonic saline-dextran solution. These two groups (MB and hypertonic saline-dextran group [MB group] and hypertonic saline-dextran-only group) of 21 animals were each compared with a group receiving isotonic saline (n = 21). MEASUREMENTS AND MAIN RESULTS: Although the groups were similar in baseline values, 4-hr survival in the MB group was increased (p = .02) in comparison with the isotonic saline group. Hemodynamic variables were somewhat improved at 15 mins after restoration of spontaneous circulation in the MB group compared with the other two groups. The jugular bulb levels of 8-isoprostane-prostaglandin F2alpha and 15-keto-dihydro-prostaglandin F2alpha (indicators of peroxidation and inflammation) were significantly decreased in the MB group compared with the isotonic saline group. Significant differences were recorded between the three groups in levels of protein S-100beta (indicator of neurologic injury), with lower levels in the MB group compared with the isotonic saline and hypertonic saline-dextran-only groups. Troponin I and myocardial muscle creatine kinase isoenzyme arterial concentrations (indicators of myocardial damage) were also significantly lower in the MB group. CONCLUSIONS: MB co-administered with a hypertonic-hyperoncotic solution increased 4-hr survival vs. saline in an experimental porcine model of cardiac arrest and reduced oxidative, inflammatory, myocardial, and neurologic injury.

Nyckelord
experimental cardiac arrest, methylene blue, saline hypertonic, circulation, survival, organ injury
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-106803 (URN)10.1097/01.CCM.0000242517.23324.27 (DOI)000241639900014 ()16957637 (PubMedID)
Tillgänglig från: 2009-07-06 Skapad: 2009-07-04 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
4. Methylene blue administration during cardio-pulmonary resuscitation and early reperfusion protects against cortical blood-brain barrier disruption
Öppna denna publikation i ny flik eller fönster >>Methylene blue administration during cardio-pulmonary resuscitation and early reperfusion protects against cortical blood-brain barrier disruption
(Engelska)Manuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
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.

Nyckelord
Methylene blue, blood brain barrier, cardiopulmonary resuscitation, cardiac arrest, nitric oxide, nitric oxide synthases
Nationell ämneskategori
Anestesi och intensivvård Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-106805 (URN)
Tillgänglig från: 2009-07-06 Skapad: 2009-07-04 Senast uppdaterad: 2015-06-09Bibliografiskt granskad

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