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Methylene Blue Administration During Cardio- Pulmonary Resuscitation and Early Reperfusion Pro- Tects Against Cortical Blood-Brain Barrier Disruption

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Methylene Blue Administration During Cardio- Pulmonary Resuscitation and Early Reperfusion Pro- Tects Against Cortical Blood-Brain Barrier Disruption Methylene blue administration during cardio- pulmonary resuscitation and early reperfusion pro- tects against cortical blood-brain barrier disruption Miclescu Adriana, Sharma Hari Shanker, Cécile Martijn, Wiklund Lars Department of Surgical Sciences/Anaesthesiology and Critical Care Medi- cine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden Objective: The present study was time. The immunohistochemistry designed to study the effects of car- analysis indicated less blood brain diac arrest and cardiopulmonary barrier disruption in the animals resuscitation (CPR) on blood-brain receiving MB (CA+MB group) barrier (BBB) permeability and sub- evidenced by decreased albumin sequent neurological injury. It also leakage (P<0.01), water content tests the cerebral effects of MB on (P=0.02), potassium (P=0.04), but the maintenance of BBB integrity, also decreased neuronal injury the production of nitric oxide (NO) (P<0.001) in this group in and regulation of nitric oxide syn- comparison with the group that was thases (NOS) in cerebral cortex. not treated with MB (CA-MB). Intervention: The control group (CA, Similarly, MB treatment reduced n=16) underwent 12 min cardiac nitrite/nitrate ratio (P=0.02), iNOS arrest without subsequent CPR, after expression (P<0.01), and nNOS which the brain of the animals was expression (P<0.01). removed immediately or after 15 and Conclusion: Cerebral edema, in- 30 min. The other two groups with 12 crease BBB permeability and neuro- min cardiac arrest and subsequent 8 logic injury are observed early in min CPR received either an infusion ischemia induced by cardiac arrest. of saline (CA-MB group, n=10) or an MB markedly reduced BBB disrup- infusion of saline with MB (CA+MB, tion and subsequent neurologic in- n= 12) started one minute after the jury. In addition with these cerebral start of CPR and continued 50 min morphologic effects, the exposure to after return of spontaneous circula- MB is associated with a decrease of tion (ROSC). In both the latter (CA- NO as measured by nitrate/nitrite MB and CA+MB) groups the brains content and partially inhibition of were removed for histological analy- NOS activity. sis at the following time points: 30, Key words: Cardiopulmonary resus- 60, 180 min after ROSC. citation (CPR); Blood-brain barrier Main Results: In all the groups an (BBB); Methylene Blue (MB); Nitric increase of necrotic neurons and oxide (NO); Nitrite/nitrate content; albumin immunoreactivity was Nitric oxide synthases (NOS) demonstrated with increasing duration of ischemia and reperfusion Introduction synthases (NOS) and consequently quantify the nitric oxide metabolite The role of the blood-brain barrier levels after global brain ischemia. We (BBB) in inducing neuronal damage previously demonstrated that the following cardiac arrest (CA) is still most serious effects on cerebral blood not well clarified. Suggested causes flow and oxygen metabolism oc- of disruption of the BBB in ischemia curred in cerebral cortex (11) that is and reperfusion are thought to be most vulnerable to ischemic insult. multifactorial and to involve effects Thus, this study focused on the of glutamate, calcium, zinc and nitric changes in BBB function and neu- oxide (NO) as well as other free radi- ronal injury in this particular cerebral cals (1). Upregulation of nitric oxide area. synthase (NOS) is associated with increased production of NO that Material and Methods induces breakdown of the BBB (2). It has been suggested that pretreatment The Uppsala Institutional Review with pharmacological agents that Board for Animal Experimentation reduce excess nitric oxide (3) or approved this prospective, rando- oxidative stress (4) might reduce mized, laboratory animal study. The disruption of BBB permeability (3, 4) piglets were handled according to the caused by ischemia/reperfusion in- guidelines of the Swedish National jury. Methylene blue (MB), a non- Board for Laboratory Animals and toxic dye and also a scavenger, re- the European Convention of Animal cently proved to be a possible aid in Care. Anesthesia was used in all resuscitation from cardiac arrest by surgical interventions. attenuating oxidative, inflammatory, myocardial and neurologic injury (5, Animals 6). The therapeutic effects of MB are ascribed to the presence of the nitric The following inclusion criteria were oxide/cyclic guanylyl mono- applied: No apparent pre-existing phosphate (NO/c-GMP) signaling disease, PaCO2 between 5-5.5 kPa, system and to its action on iron- PaO2 > 10 kPa (75 mm Hg) at base- containing enzymes. Thus, MB has line after stabilization. The animals direct inhibitory effects on nitric included in this study (n=45) were oxide synthases (7) and also blocks 12-14 weeks old and of so-called synthesis of cyclic guanosine mono- triple breed. Piglets were obtained phosphate (cGMP) by inhibiting the from a single provider source. All soluble guanylate cyclase enzyme piglets were kept fasting but had free (8). Due to xanthine oxidase inhibi- access to water during the night, and tion (9), MB also protects against the were taken to the laboratory on the toxic effects of some free oxygen morning of the experiment. radicals (10). The present study was designed to Anesthesia test the possible protective effects of Immediately upon arrival at the la- MB on maintenance of BBB integrity boratory, the animals received an after cardiac arrest and CPR. Fur- intramuscular injection of 6 mg·kg-1 ® thermore, the study tried to identify Zoletil (tiletamine and zolazepam, the potential regulation of nitric oxide Reading, France) combined with 2.2 2 mg·kg-1 Rompum® (xylazine, Bayer, Fluid administration -1 Germany) and atropine 0.04 mg·kg All animals received fluid replace- (Atropin , NM Pharma, Stockholm, ment with acetated Ringer’s solution Sweden). A peripheral venous cathe- (Ringer-acetat®, Frezenius Kabi, ter (18 Gauge) inserted in an ear vein Stockholm, Sweden) by means of an was used for induction and mainten- infusion pump (Life Care , Abbot ance of anesthesia, as well as for Shaw, USA), as follows: 30 mL·kg-1 fluid administration. All the piglets during the first hour of preparation in received an intravenous injection of order to obtain a pulmonary artery ® 20 mg morphine (Morfin Bioglan ). wedge pressure of 7-10 mm Hg, and An injection of 100 mg ketamine a continuous infusion of 10 mL·kg- ® (Ketaminol ,Veterinaria AG, Swit- 1·h-1 thereafter. zerland) was added as an intravenous bolus to achieve surgical anesthesia. Preparation and procedures The absence of motor response to An 18-G arterial catheter was ad- painful stimuli was considered indic- vanced into the aortic arch via a ative of an adequate level of anesthe- branch of the right carotid artery for sia. An intravenous infusion of 8 -1 -1 withdrawal of blood samples and mg·kg ·h sodium pentobarbital measurement of blood pressure. A (Apoteket, Sweden), morphine (Mor- 14-G saline-filled double lumen ca- phine®, Pharmacia, Uppsala, Swe- -1 -1 - theter was placed into the right den) 0.5 mg·kg ·h and 0.25 mg·kg atrium via a cutdown of the right 1·h-1 pancuronium bromide (Pavu- ® external jugular vein to measure right lon , Organon, Netherlands) dis- atrial pressure and for drug adminis- solved in 2.5% glucose solution was tration. This catheter was connected started and used for maintenance of to pressure transducers, which were anesthesia. The piglets were secured calibrated to ambient pressure at the in the supine position and were tra- level of the right atrium. cheotomized, which was done to secure a free airway during the expe- Measurements of hemody- riment. The animals were mechani- cally ventilated (Servo-i V3.1, Sie- namic variables mens Medical, Solna, Sweden) with 30% oxygen in air after preparation. During CPR and after ROSC, hemo- Volume-controlled mechanical venti- dynamic parameters including leads lation was instituted with an I: E ratio II and V5 of the ECG, heart rate of 1:2, a fixed frequency of 25/min (HR), systemic arterial blood pres- and a minute volume set to maintain sure, and right atrial pressure were arterial PaCO2 at an average of 5-5.5 continuously displayed (Solar 8000 kPa. A positive end-expiratory pres- monitor, Marquette Medical Systems, sure (PEEP) of 5 cm H2O was ap- Milwaukee, WI, USA) and recorded plied to prevent atelectasis. The cap- (Workbench 3.0, Strawberry Tree nogram and saturation level were Inc., Sunnyvale, CA, USA) until the displayed continuously until extuba- end of the experiment. tion (CO2SMO Plus-8100, Novame- Samples trix, Wallingford, CT, USA), as were Samples of arterial blood were taken leads II and V5 of the electrocardio- for blood gas analysis and acid-base gram (ECG). balance (ABL 300, Radiometer, Co- 3 penhagen, Denmark) at baseline, and J (Figure 1). If restoration of sponta- at 14, 16 and 19 min during CPR, and neous circulation (ROSC) was not after ROSC at 5, 15, 30, 60 and 120 accomplished, another two defibrilla- min, and before 180 min. Oxygen tory shocks (200 J, 360 J) and a bolus saturation and hemoglobin were injection of epinephrine 20 μg ·kg-1 determined simultaneously on an were administered. DC shocks were OSM3 Hemoximeter (Radiometer, then applied at the same energy level Copenhagen, Denmark) at the same of 360 J during a maximum period of time points. 5 min. CPR was discontinued if ROSC was not achieved during this Experimental protocol time. Restoration of spontaneous circulation was defined as return of After preparation, the piglets were co-ordinated electrical activity result- ventilated with 30% oxygen in air, ing in a systolic blood pressure great- stabilized for one hour, after which er than 60 mm Hg for at least 10 baseline measurements were obtained consecutive minutes. If the arterial before cardiac arrest. Thereafter, pH was less than 7.20 or the base ventricular fibrillation was induced deficit more than 10 mmol/L at 5 min by a 50-Hz, 40-60-V alternating after ROSC, acidosis was corrected with 1 mmol·kg-1 of a tris buffer transthoracic current applied via two ® subcutaneous needle electrodes.
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