Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation

James H. Mehaffey, Dustin Money, Eric J. Charles, Sarah Schubert, Angela Fernandez Piñeros, Di Wu, Sai Vineela Bontha, Robert Hawkins, Nicholas R. Teman, Victor E. Laubach, Valeria Mas, Curtis G. Tribble, Daniel Maluf, Ashish K. Sharma, Zequan Yang, Irving L. Kron, Mark E. Roeser

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR. SUMMARY BACKGROUND DATA: Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist. METHODS: Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups. RESULTS: Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups. CONCLUSIONS: Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.

Original languageEnglish (US)
Pages (from-to)1176-1183
Number of pages8
JournalAnnals of surgery
Volume269
Issue number6
DOIs
StatePublished - Jun 1 2019

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Purinergic P1 Receptors
Cardiopulmonary Resuscitation
Reperfusion Injury
Reperfusion
Swine
Urine
Cytokines
Troponin
Ventricular Fibrillation
Therapeutics
Microarray Analysis
Aspartate Aminotransferases
Heart Arrest
Resuscitation
Epinephrine
Lactic Acid
Anti-Inflammatory Agents
Perfusion
Kidney
Gene Expression

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Mehaffey, J. H., Money, D., Charles, E. J., Schubert, S., Piñeros, A. F., Wu, D., ... Roeser, M. E. (2019). Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation. Annals of surgery, 269(6), 1176-1183. https://doi.org/10.1097/SLA.0000000000002685

Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation. / Mehaffey, James H.; Money, Dustin; Charles, Eric J.; Schubert, Sarah; Piñeros, Angela Fernandez; Wu, Di; Bontha, Sai Vineela; Hawkins, Robert; Teman, Nicholas R.; Laubach, Victor E.; Mas, Valeria; Tribble, Curtis G.; Maluf, Daniel; Sharma, Ashish K.; Yang, Zequan; Kron, Irving L.; Roeser, Mark E.

In: Annals of surgery, Vol. 269, No. 6, 01.06.2019, p. 1176-1183.

Research output: Contribution to journalArticle

Mehaffey, JH, Money, D, Charles, EJ, Schubert, S, Piñeros, AF, Wu, D, Bontha, SV, Hawkins, R, Teman, NR, Laubach, VE, Mas, V, Tribble, CG, Maluf, D, Sharma, AK, Yang, Z, Kron, IL & Roeser, ME 2019, 'Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation', Annals of surgery, vol. 269, no. 6, pp. 1176-1183. https://doi.org/10.1097/SLA.0000000000002685
Mehaffey, James H. ; Money, Dustin ; Charles, Eric J. ; Schubert, Sarah ; Piñeros, Angela Fernandez ; Wu, Di ; Bontha, Sai Vineela ; Hawkins, Robert ; Teman, Nicholas R. ; Laubach, Victor E. ; Mas, Valeria ; Tribble, Curtis G. ; Maluf, Daniel ; Sharma, Ashish K. ; Yang, Zequan ; Kron, Irving L. ; Roeser, Mark E. / Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation. In: Annals of surgery. 2019 ; Vol. 269, No. 6. pp. 1176-1183.
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abstract = "OBJECTIVE: We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR. SUMMARY BACKGROUND DATA: Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist. METHODS: Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups. RESULTS: Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups. CONCLUSIONS: Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.",
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T1 - Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation

AU - Mehaffey, James H.

AU - Money, Dustin

AU - Charles, Eric J.

AU - Schubert, Sarah

AU - Piñeros, Angela Fernandez

AU - Wu, Di

AU - Bontha, Sai Vineela

AU - Hawkins, Robert

AU - Teman, Nicholas R.

AU - Laubach, Victor E.

AU - Mas, Valeria

AU - Tribble, Curtis G.

AU - Maluf, Daniel

AU - Sharma, Ashish K.

AU - Yang, Zequan

AU - Kron, Irving L.

AU - Roeser, Mark E.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - OBJECTIVE: We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR. SUMMARY BACKGROUND DATA: Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist. METHODS: Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups. RESULTS: Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups. CONCLUSIONS: Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.

AB - OBJECTIVE: We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR. SUMMARY BACKGROUND DATA: Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist. METHODS: Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups. RESULTS: Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups. CONCLUSIONS: Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.

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JO - Annals of Surgery

JF - Annals of Surgery

SN - 0003-4932

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ER -