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Novel Interventions in Cardiac Arrest: Targeted Temperature Management, Methylene Blue, S-PBN, Amiodarone, Milrinone and Esmolol,  Endothelin and Nitric Oxide In Porcine Resuscitation Models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Department of Operative- and Intensive Care Medicine, Hallands Hospital Halmstad, Halmstad, Sweden.ORCID iD: frank@zoerner.org
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is a major clinical problem that survival rates after out-of-hospital cardiac arrest have not markedly improved during the last decades, despite extensive research and the introduction of new interventions. However, recent studies have demonstrated promising treatments such as targeted temperature management (TTM) and methylene blue (MB).

In our first study, we investigated the effect of MB administered during experi-mental cardiopulmonary resuscitation (CPR) in the setting of postponed hypother-mia in piglets. We set out to study if MB could compensate for a delay to establish targeted TTM. The study demonstrated that MB more than compensated for 30 min delay in induction of TTM. The effect of MB added to that of TTM.

The second study examined the effects of TTM and S-PBN on the endothelin system and nitric oxide synthases (NOS) after prolonged CA in a porcine CPR mod-el. The study was designed to understand the cardioprotective mechanism of S-PBN and TTM by their influence on the endothelin system and NOS regulation. We veri-fied for the first time, that these two cardioprotective postresuscitative interventions activate endothelin-1 and its receptors concomitantly with eNOS and nNOS in the myocardium. We concluded that nitric oxide and endothelin pathways are implicated in the postresuscitative cardioprotective effects of TTM.

The third study compared survival and hemodynamic effects of low-dose amio-darone and vasopressin to vasopressin in a porcine hypovolemic CA model. The study was designed to evaluate whether resuscitation with amiodarone and vasopressin compared to vasopressin alone would have an impact on resuscitation success, survival, and hemodynamic parameters after hemorrhagic CA. We found that combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters and smaller myocardial injury compared to resuscitation with vasopressin only.

In our fourth study we planned to compare hemodynamic parameters between the treatment group (milrinone, esmolol and vasopressin; MEV) and control group (vasopressin only) during resuscitation from prolonged cardiac arrest in piglets. The study was designed to demonstrate if MEV treatment improved hemodynamics or cardiac damage compared to controls. We demonstrated that MEV treatment reduced cardiac injury compared with vasopressin alone.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2015. , 102 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1056
Keyword [en]
restoration of spontaneous circulation, ROSC, cardiopulmonary resuscitation, CPR, cardiac arrest, methylene blue, MB, S-PBN, mild therapeutic hypothermia, MTH, targeted temperature management, TTM, endothelin, ET-1, ECE-1, ETAR, ETBR, nitric oxide, NO, nitric oxide synthase, NOS, eNOS, iNOS, nNOS, porcine, amiodarone, hypovolemia, milrinone, vasopressin, esmolol, epinephrine
National Category
Anesthesiology and Intensive Care Cell and Molecular Biology Physiology Cardiac and Cardiovascular Systems
Research subject
Anaesthesiology and Intensive Care; Medical Cell Biology; Cardiology
Identifiers
URN: urn:nbn:se:uu:diva-236312ISBN: 978-91-554-9116-1 (print)OAI: oai:DiVA.org:uu-236312DiVA: diva2:763938
Public defence
2015-01-30, Hedstrandssalen, Akademiska sjukhuset, Ing. 70, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2015-01-08 Created: 2014-11-17 Last updated: 2015-02-03
List of papers
1. Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest
Open this publication in new window or tab >>Improved neuroprotective effect of methylene blue with hypothermia after porcine cardiac arrest
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2013 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 57, no 8, 1073-1082 p.Article in journal (Refereed) Published
Abstract [en]

Background

Induced mild hypothermia and administration of methylene blue (MB) have proved to have neuroprotective effects in cardiopulmonary resuscitation (CPR); however, induction of hypothermia takes time. We set out to determine if MB administered during CPR could add to the histologic neuroprotective effect of hypothermia.

Methods

A piglet model of extended cardiac arrest (12 min of untreated cardiac arrest and 8 min of CPR) was used to assess possible additional neuroprotective effects of MB when administered during CPR before mild therapeutic hypothermia induced 30 min after restoration of spontaneous circulation (ROSC). Three groups were compared: C group (n = 8) received standard CPR; PH group (n = 8) received standard CPR but 30 min after ROSC these piglets were cooled to 34°C; the PH+MB group (n = 8) received an MB infusion 1 min after commencement of CPR and the same cooling protocol as the PH group. Three hours later, the animals were killed. Immediately after death, the brains were harvested pending histological and immunohistological analysis.

Results

Circulatory variables were similar in the groups except that cardiac output was greater in the PH+MB group 2–3 h after ROSC. Cerebral cortical neuronal injury and blood–brain barrier disruption was greatest in the C group and least in the MB group. The neuroprotective effect of MB and hypothermia was significantly greater than that of delayed hypothermia alone.

Conclusion

Administration of MB during CPR added to the short term neuroprotective effects of induced mild hypothermia induced 30 min after ROSC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-199854 (URN)10.1111/aas.12106 (DOI)000323075000017 ()23577658 (PubMedID)
Available from: 2013-05-17 Created: 2013-05-17 Last updated: 2017-12-06Bibliographically approved
2. Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation
Open this publication in new window or tab >>Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, e64792- p.Article in journal (Refereed) Published
Abstract [en]

Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-200585 (URN)10.1371/journal.pone.0064792 (DOI)000319435600076 ()23717659 (PubMedID)
Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-12-06Bibliographically approved
3. Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs
Open this publication in new window or tab >>Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs
2014 (English)In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, Vol. 76, no 6, 1402-1408 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets. METHODS: Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation. RESULTS: Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group. CONCLUSION: Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

Keyword
Amiodarone, cardiac arrest, ventricular fibrillation, hemorrhage, pigs
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-228547 (URN)10.1097/TA.0000000000000243 (DOI)000337145500011 ()
Available from: 2014-07-17 Created: 2014-07-16 Last updated: 2015-02-03Bibliographically approved
4. Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest
Open this publication in new window or tab >>Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

Methods: Twenty-six immature male piglets were subjected to 12 min VF followed by 8 min CPR. The treatment group (n=13) received i.v. boluses vasopressin 0.4 U∙kg−1, esmolol 250 μg∙kg−1 and milrinone 25 μg∙kg−1 after 13 min, followed by i.v. boluses esmolol 375 μg∙kg−1 and milrinone 25 μg∙kg−1 after 18 min and continuous esmolol 15 μg∙kg−1∙h−1 infusion during 180 min reperfusion, while controls (n=13) received equal amounts of vasopressin and saline. A 200J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200J defibrillation and bolus vasopressin 0.4 U∙kg−1 were administered in both groups. DC shocks at 360J were applied as one shot min−1 over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

Results: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (p<0.05). The treatment group received less norepinephrine (p<0.01) and had greater diuresis (p<0.01). There was no difference in survival between groups.

Conclusions: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone. 

Keyword
Cardiac arrest, resumption of spontaneous circulation, ROSC, milrinone, vasopressin, esmolol, I/R injury, reperfusion injury, cardioprotection, myocardial ischemia, epinephrine, resuscitation
National Category
Anesthesiology and Intensive Care Medical and Health Sciences
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-237869 (URN)
Available from: 2014-12-06 Created: 2014-12-06 Last updated: 2015-06-11

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