Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution

Eduardo C. Ayuste, Huazhen Chen, Elena Koustova, Peter M Rhee, Naresh Ahuja, Zhang Chen, C. Robert Valeri, Konstantinos Spaniolas, Tina Mehrani, Hasan B. Alam, David B. Hoyt, Joseph J. Tepas, Raul Coimbra

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Background: Cytotoxic properties of racemic (D-,L-isomers) lactated Ringer's solution detected in vitro and in small animal experiments, have not been confirmed in large animal models. Our hypothesis was that in a clinically relevant large animal model of hemorrhage, resuscitation with racemic lactated Ringer's solution would induce cellular apoptosis, which can be attenuated by elimination of D-lactate. Methods: Yorkshire swine (n = 49, weight 40-58 kg) were subjected to uncontrolled (iliac arterial and venous injuries) and controlled hemorrhage, totaling 40% of estimated blood volume. They were randomized (n = 7/group) to control groups, which consisted of (1) no hemorrhage (NH), (2) no resuscitation (NR), or resuscitation groups, which consisted of (3) 0.9% saline (NS), (4) racemic lactated Ringer's (DL-LR), (5) L-isomer lactated Ringer's (L-LR), (6) Ketone Ringer's (KR), (7) 6% hetastarch in 0.9% saline (Hespan). KR was identical to LR except for equimolar substitution of lactate with beta-hydroxybutyrate. Resuscitation was performed in three phases, simulating (1) prehospital, (2) operative, (3) postoperative/recovery periods. Arterial blood gasses, circulating cytokines (TNF-α, IL-1, -6, -10), and markers of organ injury were serially measured. Metabolic activity of brain, and liver, was measured with microdialysis. Four hours postinjury, organs were harvested for Western blotting, ELISA, TUNEL assay, and immunohistochemistry. Results: All resuscitation strategies restored blood pressure, but clearance of lactic acidosis was impeded following DL-LR resuscitation. Metabolic activity decreased during shock and improved with resuscitation, without any significant inter-group differences. Levels of cytokines in circulation were similar, but tissue levels of TNF in liver and lung increased six- and threefolds (p < 0.05) in NR group. In liver, all resuscitation strategies significantly decreased TNF levels compared with the NR group, but in the lung resuscitation with lactated Ringer (DL and L isomers) failed to decrease tissue TNF levels. DL-LR resuscitation also increased apoptosis (p < 0.05) in liver and lung, which was not seen after resuscitation with other solutions. Conclusions: In this large animal model of hemorrhagic shock, resuscitation with conventional (racemic) LR solution increased apoptotic cell death in liver and lung. This effect can be prevented by simple elimination of D-lactate from the Ringer's solution.

Original languageEnglish (US)
Pages (from-to)52-63
Number of pages12
JournalJournal of Trauma
Volume60
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Fingerprint

Hemorrhagic Shock
Resuscitation
Swine
Apoptosis
Lung
Liver
Hydroxyethyl Starch Derivatives
Lactic Acid
Animal Models
Hemorrhage
Ringer's solution
Ketones
Cytokines
Lactic Acidosis
3-Hydroxybutyric Acid
Microdialysis
In Situ Nick-End Labeling
Wounds and Injuries
Blood Volume
Interleukin-1

Keywords

  • Apoptosis
  • Cytokines
  • Hemorrhage
  • Ketone
  • Liver
  • Lung
  • Metabolism
  • Resuscitation
  • Ringers solutions
  • Swine

ASJC Scopus subject areas

  • Surgery

Cite this

Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution. / Ayuste, Eduardo C.; Chen, Huazhen; Koustova, Elena; Rhee, Peter M; Ahuja, Naresh; Chen, Zhang; Valeri, C. Robert; Spaniolas, Konstantinos; Mehrani, Tina; Alam, Hasan B.; Hoyt, David B.; Tepas, Joseph J.; Coimbra, Raul.

In: Journal of Trauma, Vol. 60, No. 1, 01.2006, p. 52-63.

Research output: Contribution to journalArticle

Ayuste, EC, Chen, H, Koustova, E, Rhee, PM, Ahuja, N, Chen, Z, Valeri, CR, Spaniolas, K, Mehrani, T, Alam, HB, Hoyt, DB, Tepas, JJ & Coimbra, R 2006, 'Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution', Journal of Trauma, vol. 60, no. 1, pp. 52-63. https://doi.org/10.1097/01.ta.0000200156.05397.0b
Ayuste, Eduardo C. ; Chen, Huazhen ; Koustova, Elena ; Rhee, Peter M ; Ahuja, Naresh ; Chen, Zhang ; Valeri, C. Robert ; Spaniolas, Konstantinos ; Mehrani, Tina ; Alam, Hasan B. ; Hoyt, David B. ; Tepas, Joseph J. ; Coimbra, Raul. / Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution. In: Journal of Trauma. 2006 ; Vol. 60, No. 1. pp. 52-63.
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TY - JOUR

T1 - Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution

AU - Ayuste, Eduardo C.

AU - Chen, Huazhen

AU - Koustova, Elena

AU - Rhee, Peter M

AU - Ahuja, Naresh

AU - Chen, Zhang

AU - Valeri, C. Robert

AU - Spaniolas, Konstantinos

AU - Mehrani, Tina

AU - Alam, Hasan B.

AU - Hoyt, David B.

AU - Tepas, Joseph J.

AU - Coimbra, Raul

PY - 2006/1

Y1 - 2006/1

N2 - Background: Cytotoxic properties of racemic (D-,L-isomers) lactated Ringer's solution detected in vitro and in small animal experiments, have not been confirmed in large animal models. Our hypothesis was that in a clinically relevant large animal model of hemorrhage, resuscitation with racemic lactated Ringer's solution would induce cellular apoptosis, which can be attenuated by elimination of D-lactate. Methods: Yorkshire swine (n = 49, weight 40-58 kg) were subjected to uncontrolled (iliac arterial and venous injuries) and controlled hemorrhage, totaling 40% of estimated blood volume. They were randomized (n = 7/group) to control groups, which consisted of (1) no hemorrhage (NH), (2) no resuscitation (NR), or resuscitation groups, which consisted of (3) 0.9% saline (NS), (4) racemic lactated Ringer's (DL-LR), (5) L-isomer lactated Ringer's (L-LR), (6) Ketone Ringer's (KR), (7) 6% hetastarch in 0.9% saline (Hespan). KR was identical to LR except for equimolar substitution of lactate with beta-hydroxybutyrate. Resuscitation was performed in three phases, simulating (1) prehospital, (2) operative, (3) postoperative/recovery periods. Arterial blood gasses, circulating cytokines (TNF-α, IL-1, -6, -10), and markers of organ injury were serially measured. Metabolic activity of brain, and liver, was measured with microdialysis. Four hours postinjury, organs were harvested for Western blotting, ELISA, TUNEL assay, and immunohistochemistry. Results: All resuscitation strategies restored blood pressure, but clearance of lactic acidosis was impeded following DL-LR resuscitation. Metabolic activity decreased during shock and improved with resuscitation, without any significant inter-group differences. Levels of cytokines in circulation were similar, but tissue levels of TNF in liver and lung increased six- and threefolds (p < 0.05) in NR group. In liver, all resuscitation strategies significantly decreased TNF levels compared with the NR group, but in the lung resuscitation with lactated Ringer (DL and L isomers) failed to decrease tissue TNF levels. DL-LR resuscitation also increased apoptosis (p < 0.05) in liver and lung, which was not seen after resuscitation with other solutions. Conclusions: In this large animal model of hemorrhagic shock, resuscitation with conventional (racemic) LR solution increased apoptotic cell death in liver and lung. This effect can be prevented by simple elimination of D-lactate from the Ringer's solution.

AB - Background: Cytotoxic properties of racemic (D-,L-isomers) lactated Ringer's solution detected in vitro and in small animal experiments, have not been confirmed in large animal models. Our hypothesis was that in a clinically relevant large animal model of hemorrhage, resuscitation with racemic lactated Ringer's solution would induce cellular apoptosis, which can be attenuated by elimination of D-lactate. Methods: Yorkshire swine (n = 49, weight 40-58 kg) were subjected to uncontrolled (iliac arterial and venous injuries) and controlled hemorrhage, totaling 40% of estimated blood volume. They were randomized (n = 7/group) to control groups, which consisted of (1) no hemorrhage (NH), (2) no resuscitation (NR), or resuscitation groups, which consisted of (3) 0.9% saline (NS), (4) racemic lactated Ringer's (DL-LR), (5) L-isomer lactated Ringer's (L-LR), (6) Ketone Ringer's (KR), (7) 6% hetastarch in 0.9% saline (Hespan). KR was identical to LR except for equimolar substitution of lactate with beta-hydroxybutyrate. Resuscitation was performed in three phases, simulating (1) prehospital, (2) operative, (3) postoperative/recovery periods. Arterial blood gasses, circulating cytokines (TNF-α, IL-1, -6, -10), and markers of organ injury were serially measured. Metabolic activity of brain, and liver, was measured with microdialysis. Four hours postinjury, organs were harvested for Western blotting, ELISA, TUNEL assay, and immunohistochemistry. Results: All resuscitation strategies restored blood pressure, but clearance of lactic acidosis was impeded following DL-LR resuscitation. Metabolic activity decreased during shock and improved with resuscitation, without any significant inter-group differences. Levels of cytokines in circulation were similar, but tissue levels of TNF in liver and lung increased six- and threefolds (p < 0.05) in NR group. In liver, all resuscitation strategies significantly decreased TNF levels compared with the NR group, but in the lung resuscitation with lactated Ringer (DL and L isomers) failed to decrease tissue TNF levels. DL-LR resuscitation also increased apoptosis (p < 0.05) in liver and lung, which was not seen after resuscitation with other solutions. Conclusions: In this large animal model of hemorrhagic shock, resuscitation with conventional (racemic) LR solution increased apoptotic cell death in liver and lung. This effect can be prevented by simple elimination of D-lactate from the Ringer's solution.

KW - Apoptosis

KW - Cytokines

KW - Hemorrhage

KW - Ketone

KW - Liver

KW - Lung

KW - Metabolism

KW - Resuscitation

KW - Ringers solutions

KW - Swine

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