Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats

Cecilia E. Perez de Lara Rodriguez; Lester R Drewes; Matthew T. Andrews

doi:10.1007/s00360-017-1076-7

Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats

Cecilia E. Perez de Lara Rodriguez, Lester R Drewes, Matthew T. Andrews

Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

A small-volume (1 ml/kg) resuscitation fluid based on metabolic adaptations in hibernating mammals was optimized using a rat model of hemorrhagic shock. A previous study of this therapy tested only one concentration of three specific components: 4 M D-stereoisomer of beta-hydroxybutyrate (BHB), 43 mM melatonin, and 20% DMSO. In this study, we considered the range of concentrations of BHB and melatonin seen during the physiological extremes of rapid arousal from hypothermic torpor in natural hibernators and applied these to the non-hibernating Sprague–Dawley rat model. These extremes normally result in ischemia and reperfusion injury in non-hibernating mammals. Dose-ranging studies were conducted for BHB and melatonin in rats with 60% blood loss. BHB was administered at either 4, 2, or 0.4 M concentration in conjunction with 4.3 mM melatonin and 10% DMSO. Subsequently, melatonin was administered at either 4.3, 0.43, 0.0043, 0.000043, or 0 mM in conjunction with 4 M BHB and 2% DMSO. 10-day mean survival showed a dose-dependent trend: rats survived longer with higher concentration of infused BHB (4 M BHB, 7.38 ± 1.75 days; 2 M BHB, 5.25 ± 2.22 days; 0.4 M BHB, 2.07 ± 2.05 days). Administering 4 M BHB without melatonin resulted in low mean survival times (4.38 ± 1.42 days). All treatments containing both 4 M BHB and melatonin, regardless of melatonin concentration, resulted in mean survival times of ~7.5 days. We conclude there is a dose-dependent trend in which higher BHB concentration resulted in improved survival over 10 days.

Original language	English (US)
Pages (from-to)	769-778
Number of pages	10
Journal	Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology
Volume	187
Issue number	5-6
DOIs	https://doi.org/10.1007/s00360-017-1076-7
State	Published - Jul 1 2017

Bibliographical note

Funding Information:
We would like to thank the U.S. Army Medical Research and Materiel Command (Grant W81XWH-11-1-0409) for financial support. Very special recognition goes to Dr. Ronald Regal of Mathematics and Statistics Department at the University of Minnesota Duluth, for all of his guidance with statistical analyses. We also thank Alison Kingsbury, Krysta Nelson, and Matt Donohue of the Andrews laboratory as well as Ms. Kristine Mulier and Dr. Gregory Beilman of the Department of Surgery at the University of Minnesota.

Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.

Keywords

Beta-hydroxybutyrate
Fluid resuscitation
Hemorrhage
Hibernation
Ketone
Melatonin

Access

10.1007/s00360-017-1076-7

Cite this

Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats. / Perez de Lara Rodriguez, Cecilia E.; Drewes, Lester R; Andrews, Matthew T.

In: Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology, Vol. 187, No. 5-6, 01.07.2017, p. 769-778.

Research output: Contribution to journal › Article › peer-review

@article{dbd4de7b9af5472b81cf2af7187be74a,

title = "Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats",

abstract = "A small-volume (1 ml/kg) resuscitation fluid based on metabolic adaptations in hibernating mammals was optimized using a rat model of hemorrhagic shock. A previous study of this therapy tested only one concentration of three specific components: 4 M D-stereoisomer of beta-hydroxybutyrate (BHB), 43 mM melatonin, and 20% DMSO. In this study, we considered the range of concentrations of BHB and melatonin seen during the physiological extremes of rapid arousal from hypothermic torpor in natural hibernators and applied these to the non-hibernating Sprague–Dawley rat model. These extremes normally result in ischemia and reperfusion injury in non-hibernating mammals. Dose-ranging studies were conducted for BHB and melatonin in rats with 60% blood loss. BHB was administered at either 4, 2, or 0.4 M concentration in conjunction with 4.3 mM melatonin and 10% DMSO. Subsequently, melatonin was administered at either 4.3, 0.43, 0.0043, 0.000043, or 0 mM in conjunction with 4 M BHB and 2% DMSO. 10-day mean survival showed a dose-dependent trend: rats survived longer with higher concentration of infused BHB (4 M BHB, 7.38 ± 1.75 days; 2 M BHB, 5.25 ± 2.22 days; 0.4 M BHB, 2.07 ± 2.05 days). Administering 4 M BHB without melatonin resulted in low mean survival times (4.38 ± 1.42 days). All treatments containing both 4 M BHB and melatonin, regardless of melatonin concentration, resulted in mean survival times of ~7.5 days. We conclude there is a dose-dependent trend in which higher BHB concentration resulted in improved survival over 10 days.",

keywords = "Beta-hydroxybutyrate, Fluid resuscitation, Hemorrhage, Hibernation, Ketone, Melatonin",

author = "{Perez de Lara Rodriguez}, {Cecilia E.} and Drewes, {Lester R} and Andrews, {Matthew T.}",

note = "Funding Information: We would like to thank the U.S. Army Medical Research and Materiel Command (Grant W81XWH-11-1-0409) for financial support. Very special recognition goes to Dr. Ronald Regal of Mathematics and Statistics Department at the University of Minnesota Duluth, for all of his guidance with statistical analyses. We also thank Alison Kingsbury, Krysta Nelson, and Matt Donohue of the Andrews laboratory as well as Ms. Kristine Mulier and Dr. Gregory Beilman of the Department of Surgery at the University of Minnesota. Publisher Copyright: {\textcopyright} 2017, Springer-Verlag Berlin Heidelberg.",

year = "2017",

month = jul,

day = "1",

doi = "10.1007/s00360-017-1076-7",

language = "English (US)",

volume = "187",

pages = "769--778",

journal = "Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology",

issn = "0174-1578",

publisher = "Springer Verlag",

number = "5-6",

}

TY - JOUR

T1 - Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats

AU - Perez de Lara Rodriguez, Cecilia E.

AU - Drewes, Lester R

AU - Andrews, Matthew T.

N1 - Funding Information: We would like to thank the U.S. Army Medical Research and Materiel Command (Grant W81XWH-11-1-0409) for financial support. Very special recognition goes to Dr. Ronald Regal of Mathematics and Statistics Department at the University of Minnesota Duluth, for all of his guidance with statistical analyses. We also thank Alison Kingsbury, Krysta Nelson, and Matt Donohue of the Andrews laboratory as well as Ms. Kristine Mulier and Dr. Gregory Beilman of the Department of Surgery at the University of Minnesota. Publisher Copyright: © 2017, Springer-Verlag Berlin Heidelberg.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - A small-volume (1 ml/kg) resuscitation fluid based on metabolic adaptations in hibernating mammals was optimized using a rat model of hemorrhagic shock. A previous study of this therapy tested only one concentration of three specific components: 4 M D-stereoisomer of beta-hydroxybutyrate (BHB), 43 mM melatonin, and 20% DMSO. In this study, we considered the range of concentrations of BHB and melatonin seen during the physiological extremes of rapid arousal from hypothermic torpor in natural hibernators and applied these to the non-hibernating Sprague–Dawley rat model. These extremes normally result in ischemia and reperfusion injury in non-hibernating mammals. Dose-ranging studies were conducted for BHB and melatonin in rats with 60% blood loss. BHB was administered at either 4, 2, or 0.4 M concentration in conjunction with 4.3 mM melatonin and 10% DMSO. Subsequently, melatonin was administered at either 4.3, 0.43, 0.0043, 0.000043, or 0 mM in conjunction with 4 M BHB and 2% DMSO. 10-day mean survival showed a dose-dependent trend: rats survived longer with higher concentration of infused BHB (4 M BHB, 7.38 ± 1.75 days; 2 M BHB, 5.25 ± 2.22 days; 0.4 M BHB, 2.07 ± 2.05 days). Administering 4 M BHB without melatonin resulted in low mean survival times (4.38 ± 1.42 days). All treatments containing both 4 M BHB and melatonin, regardless of melatonin concentration, resulted in mean survival times of ~7.5 days. We conclude there is a dose-dependent trend in which higher BHB concentration resulted in improved survival over 10 days.

AB - A small-volume (1 ml/kg) resuscitation fluid based on metabolic adaptations in hibernating mammals was optimized using a rat model of hemorrhagic shock. A previous study of this therapy tested only one concentration of three specific components: 4 M D-stereoisomer of beta-hydroxybutyrate (BHB), 43 mM melatonin, and 20% DMSO. In this study, we considered the range of concentrations of BHB and melatonin seen during the physiological extremes of rapid arousal from hypothermic torpor in natural hibernators and applied these to the non-hibernating Sprague–Dawley rat model. These extremes normally result in ischemia and reperfusion injury in non-hibernating mammals. Dose-ranging studies were conducted for BHB and melatonin in rats with 60% blood loss. BHB was administered at either 4, 2, or 0.4 M concentration in conjunction with 4.3 mM melatonin and 10% DMSO. Subsequently, melatonin was administered at either 4.3, 0.43, 0.0043, 0.000043, or 0 mM in conjunction with 4 M BHB and 2% DMSO. 10-day mean survival showed a dose-dependent trend: rats survived longer with higher concentration of infused BHB (4 M BHB, 7.38 ± 1.75 days; 2 M BHB, 5.25 ± 2.22 days; 0.4 M BHB, 2.07 ± 2.05 days). Administering 4 M BHB without melatonin resulted in low mean survival times (4.38 ± 1.42 days). All treatments containing both 4 M BHB and melatonin, regardless of melatonin concentration, resulted in mean survival times of ~7.5 days. We conclude there is a dose-dependent trend in which higher BHB concentration resulted in improved survival over 10 days.

KW - Beta-hydroxybutyrate

KW - Fluid resuscitation

KW - Hemorrhage

KW - Hibernation

KW - Ketone

KW - Melatonin

UR - http://www.scopus.com/inward/record.url?scp=85015742905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015742905&partnerID=8YFLogxK

U2 - 10.1007/s00360-017-1076-7

DO - 10.1007/s00360-017-1076-7

M3 - Article

C2 - 28324159

AN - SCOPUS:85015742905

VL - 187

SP - 769

EP - 778

JO - Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology

JF - Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology

SN - 0174-1578

IS - 5-6

ER -

Hibernation-based blood loss therapy increases survivability of lethal hemorrhagic shock in rats

Abstract

Bibliographical note

Keywords

Access

Other files and links

Fingerprint

Cite this