Methylene blue as an adjuvant during cardiopulmonary resuscitation: an experimental study in rats
Azul de metileno como adjuvante na reanimação cardiopulmonar: estudo experimental em ratos
Marcelo Souza Xavier, Matheus F. Vane, Roberta F. Vieira, Cristiano C. Oliveira, Debora R.R. Maia, Leticia U.C. de Castro, Maria José Carvalho Carmona, José Otávio Costa Auler Jr., Denise Aya Otsuki
Abstract
Introduction
Methylene Blue (MB) has been shown to attenuate oxidative, inflammatory, myocardial, and neurological lesions during ischemia-reperfusion and has great potential during cardiac arrest. This study aimed to determine the effects of MB combined with epinephrine during cardiac arrest on myocardial and cerebral lesions.
Method
Thirty-eight male Wistar rats were randomly assigned to four groups: the sham group (SH, n = 5), and three groups subjected to cardiac arrest (n = 11/group) and treated with EPI 20 µg.kg−1 (EPI), EPI 20 µg.kg−1 + MB 2 mg.kg−1 (EPI + MB), or saline 0.9% 0.2 ml (CTL). Ventricular fibrillation was induced by direct electrical stimulation in the right ventricle for 3 minutes, and anoxia was maintained for 5 minutes. Cardiopulmonary Resuscitation (CPR) consisted of medications, ventilation, chest compressions, and defibrillation. After returning to spontaneous circulation, animals were observed for four hours. Blood gas, troponin, oxidative stress, histology, and TUNEL stainingmeasurements were analyzed. Groups were compared using generalized estimating equations.
Results
No differences in the Returning of Spontaneous Circulation (ROSC) rate were observed among the groups (EPI: 63%, EPI + MB: 45%, CTL: 40%, p = 0.672). The mean arterial pressure immediately after ROSC was higher in the EPI+MB group than in the CTRL group (CTL: 30.5 [5.8], EPI: 63 [25.5], EPI+MB: 123 [31] mmHg, p = 0.007). Serum troponin levels were high in the CTL group (CTL: 130.1 [333.8], EPI: 3.70 [36.0], EPI + MB: 43.7 [116.31] ng/mL, p < 0.05).
Conclusion
The coadministration of MB and epinephrine failed to yield enhancements in cardiac or brain lesions in a rodent model of cardiac arrest.
Keywords
Resumo
Introdução
Foi demonstrado que o azul de metileno (AM) atenua lesões oxidativas, inflamatórias, miocárdicas e neurológicas durante a isquemia-reperfusão e tem grande potencial durante a parada cardíaca. Este estudo teve como objetivo determinar os efeitos do AM combinado com epinefrina durante parada cardíaca nas lesões miocárdicas e cerebrais.
Métodos
Trinta e oito ratos Wistar machos foram distribuídos aleatoriamente em quatro grupos: o grupo placebo (SH, n = 5) e três grupos submetidos a parada cardíaca (n = 11/grupo) e tratados com EPI 20 µg.kg−1 (EPI ), EPI 20 µg.kg−1 + MB 2 mg.kg−1 (EPI + MB) ou solução salina 0,9% 0,2 ml (CTL). A fibrilação ventricular foi induzida por estimulação elétrica direta no ventrículo direito por 3 minutos e a anóxia foi mantida por 5 minutos. A ressuscitação cardiopulmonar (RCP) consistiu em medicamentos, ventilação, compressões torácicas e desfibrilação. Após retornarem à circulação espontânea, os animais foram observados por quatro horas. Foram analisadas medidas de gasometria arterial, troponina, estresse oxidativo, histologia e coloração TUNEL. Os grupos foram comparados usando equações de estimativa generalizadas.
Resultados
Não foram observadas diferenças na taxa de Retorno da Circulação Espontânea (RCE) entre os grupos (EPI: 63%, EPI + AM: 45%, CTL: 40%, p = 0,672). A pressão arterial média imediatamente após o RCE foi maior no grupo EPI+AM do que no grupo CTRL (CTL: 30,5 [5,8], EPI: 63 [25,5], EPI+AM: 123 [31] mmHg, p = 0,007). Os níveis séricos de troponina estavam elevados no grupo CTL (CTL: 130,1 [333,8], EPI: 3,70 [36,0], EPI + AM: 43,7 [116,31] ng/mL, p < 0,05).
Conclusão
A coadministração de AM e epinefrina não conseguiu produzir melhorias nas lesões cardíacas ou cerebrais em um modelo de parada cardíaca em roedores.
Palavras-chave
References
1. Panchal AR, Chair JAB, Cabanas JG, et al. Part 3: Adult Basic ~ and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142:366−468.
2. Lin S, Callaway CW, Shah PS, et al. Adrenaline for out-of-hospital cardiac arrest resuscitation: a systematic review and metaanalysis of randomized controlled trials. Resuscitation. 2014;85:732−40.
3. da Luz VF, Otsuki DA, Gonzalez MM, et al. Myocardial protection induced by fentanyl in pigs exposed to high-dose Adrenaline. Clin Exp Pharmacol Physiol. 2015;42:1098−107.
4. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of- hospital cardiac arrest. JAMA. 2012;307:1161−8.
5. Jentzer JC, Clements CM, Murphy JG, Scott Wright R. Recent developments in the management of patients resuscitated from cardiac arrest. J Crit Care. 2017;39:97−107.
6. Jang DH, Nelson LS, Hoffman RS. Methylene blue in the treatment of refractory shock from an amlodipine overdose. Ann Emerg Med. 2011;58:565−7.
7. Rajah GB, Ding Y. Experimental neuroprotection in ischemic stroke: a concise review. Neurosurg Focus. 2017;42:E2.
8. Miranda LE, Mente E^D, Molina CAF, et al. Methylene blue and the NO/cGMP pathway in solid organs transplants. Minerva Anestesiol. 2020;86:423−32.
9. Miclescu A, Basu S, Wiklund L. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest. Crit Care Med. 2006;34:2806−13.
10. Wiklund L, Zoerner F, Semenas E, Miclescu A, Basu S, Sharma HS. Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest. Acta Anaesthesiol Scand. 2013;57:1073−82.
11. Lamoureux L, Radhakrishnan J, Gazmuri RJ. A Rat Model of Ventricular Fibrillation and Resuscitation by Conventional Closedchest Technique. J Vis Exp. 2015;98:52413.
12. Vane MF, Carmona MJC, Otsuki DA, et al. Cardiac arrest animal model: a simple device for small animals’ chest compression. Rev Bras Anestesiol. 2017;67:440−1.
13. Krieter H, Denz C, Janke C, et al. Hypertonic- hyperoncotic solutions reduce the release of cardiac troponin I and s-100 after successful cardiopulmonary resuscitation in pigs. Anesth Analg. 2002;95:1031−6.
14. Bertsch T, Janke C, Denz C, et al. Cardiac troponin I and cardiac troponin T increases in pigs during ischemia-reperfusion damage. Exp Toxicol Pathol. 2000;52:157−9.
15. Bertsch T, Denz C, Janke C, et al. Hypertonic-hyperoncotic solutions decrease cardiac troponin I concentrations in peripheral blood in a porcine ischemia-reperfusion model. Exp Toxicol Pathol. 2001;53:153−6.
16. Tatsumi T, Akashi K, Keira N, et al. Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts. J Mol Cell Cardiol. 2004;37:775−84.
17. Preiser JC, Lejeune P, Roman A, et al. Methylene blue administration in septic shock: a clinical trial. Crit. Care Med. 1995;23:259−64.
18. Naoum EE, Dalia AA, Roberts RJ, et al. Methylene blue for vasodilatory shock in the intensive care unit: a retrospective, observational study. BMC Anesthesiol. 2022;22:199−215.
19. Stub D, Bernard S, Duffy SJ, Kaye DM. Post cardiac arrest syndrome: a review of therapeutic strategies. Circulation. 2011;123:1428−35.
20. Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, Spaulding C. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care. 2004;10:208−12.
21. Nolan JP, Sandroni C, Bottiger BW, et al. European Resuscitation € Council and European Society of Intensive Care Medicine Guidelines 2021: Post-resuscitation care. Resuscitation. 2021;161:220 −69.
22. Gough CJR, Nolan JP. The role of Adrenaline in cardiopulmonary resuscitation. Crit Care. 2018;29(22):139.
23. Attaran RR, Ewy GA. Epinephrine in resuscitation: curse or cure? Future Cardiol. 2010;6:473−82.
24. Juffermans NP, Vervloet MG, Daemen-Gubbels CR, Binnekade JM, de Jong M, Groeneveld AB. A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock. Nitric Oxide. 2010;22:275−80.
25. Lu Q, Tucker D, Dong Y, Zhao N, Zhang Q. Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia. Mol Neurobiol. 2016;53:5344−55.
26. Sharma HS, Miclescu A, Wiklund L. Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. J Neural Transm. 2011;118:87−114.
27. Senthilnathan M, Cherian A, Balachander H, Maroju NK. Role of Methylene Blue in the Maintenance of Postinduction Hemodynamic Status in Patients with Perforation Peritonitis: A Pilot Study. Anesth Essays Res. 2017;11:665−9.
28. Wiklund L, Basu S, Miclescu A, Wiklund P, Ronquist G, Sharma HS. Neuro- and cardioprotective effects of blockade of nitric oxide action by administration of methylene blue. Ann N Y Acad Sci. 2007;1122:231−44.
29. Figueroa XF, Poblete I, Fernandez R, Pedemonte C, Cort es V, Huidobro-Toro JP. NO production and eNOS phosphorylation induced by Epinephrine through the activation of beta-adrenoceptors. Am J Physiol Heart Circ Physiol. 2009;297:H134−43.
30. Porizka M, Kopecky P, Dvorakova H, et al. Methylene blue administration in patients with refractory distributive shock ‒ a retrospective study. Sci Rep. 2020;10:1828.
Submitted date:
05/15/2023
Accepted date:
10/13/2023
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email