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For: Carrillo P, Takasu A, Safar P, Tisherman S, Stezoski SW, Stolz G, Dixon CE, Radovsky A. Prolonged severe hemorrhagic shock and resuscitation in rats does not cause subtle brain damage. J Trauma 1998;45:239-48; discussion 248-9. [PMID: 9715179 DOI: 10.1097/00005373-199808000-00007] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]

For:	Carrillo P, Takasu A, Safar P, Tisherman S, Stezoski SW, Stolz G, Dixon CE, Radovsky A. Prolonged severe hemorrhagic shock and resuscitation in rats does not cause subtle brain damage. J Trauma 1998;45:239-48; discussion 248-9. [PMID: 9715179 DOI: 10.1097/00005373-199808000-00007] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]

Number

Cited by Other Article(s)

Magnet I, Stommel AM, Schriefl C, Mueller M, Poppe M, Grafeneder J, Testori C, Janata A, Schober A, Grassmann D, Behringer W, Weihs W, Holzer M, Hoegler S, Ettl F. Neuroprotection with hypothermic reperfusion and extracorporeal cardiopulmonary resuscitation - A randomized controlled animal trial of prolonged ventricular fibrillation cardiac arrest in rats. J Cereb Blood Flow Metab 2025;45:476-485. [PMID: 39246100 PMCID: PMC11574926 DOI: 10.1177/0271678x241281485] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/31/2024] [Accepted: 08/15/2024] [Indexed: 09/10/2024]

Stommel AM, Högler S, Mueller M, Magnet IAM, Kodajova P, Ullram B, Szinovatz A, Panzer FP, Engenhart-Seyrl A, Kaschmekat J, Schütz T, Holzer M, Weihs W. A ventricular fibrillation cardiac arrest model with extracorporeal cardiopulmonary resuscitation in rats: 8 minutes arrest time leads to increased myocardial damage but does not increase neuronal damage compared to 6 minutes. Front Vet Sci 2023;10:1276588. [PMID: 38026669 PMCID: PMC10655001 DOI: 10.3389/fvets.2023.1276588] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open

Abstract

Introduction

Extracorporeal cardiopulmonary resuscitation (ECPR) is an emerging strategy in highly selected patients with refractory cardiac arrest (CA). Animal models can help to identify new therapeutic strategies to improve neurological outcome and cardiac function after global ischemia in CA. Aim of the study was to establish a reproducible ECPR rat model of ventricular fibrillation CA (VFCA) that leads to consistent neuronal damage with acceptable long-term survival rates, which can be used for future research.

Materials and methods

Male Sprague Dawley rats were resuscitated with ECPR from 6 min (n = 15) and 8 min (n = 16) VFCA. Animals surviving for 14 days after return of spontaneous resuscitation (ROSC) were compared with sham operated animals (n = 10); neurological outcome was assessed daily until day 14. In the hippocampal cornu ammonis 1 region viable neurons were counted. Microglia and astrocyte reaction was assessed by Iba1 and GFAP immunohistochemistry, and collagen fibers in the myocardium were detected in Azan staining. QuPath was applied for quantification.

Results

Of the 15 rats included in the 6 min CA group, all achieved ROSC (100%) and 10 (67%) survived to 14 days; in the 8 min CA group, 15 (94%) achieved ROSC and 5 (31%) reached the endpoint. All sham animals (n = 10) survived 2 weeks. The quantity of viable neurons was significantly decreased, while the area displaying Iba1 and GFAP positive pixels was significantly increased in the hippocampus across both groups that experienced CA. Interestingly, there was no difference between the two CA groups regarding these changes. The myocardium in the 8 min CA group exhibited significantly more collagen fibers compared to the sham animals, without differences between 6- and 8-min CA groups. However, this significant increase was not observed in the 6 min CA group.

Conclusion

Our findings indicate a uniform occurrence of neuronal damage in the hippocampus across both CA groups. However, there was a decrease in survival following an 8-min CA. Consequently, a 6-min duration of CA resulted in predictable neurological damage without significant cardiac damage and ensured adequate survival rates up to 14 days. This appears to offer a reliable model for investigating neuroprotective therapies.

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Jakobsen RP, Nielsen TH, Mølstrøm S, Nordström CH, Granfeldt A, Toft P. Moderately prolonged permissive hypotension results in reversible metabolic perturbation evaluated by intracerebral microdialysis - an experimental animal study. Intensive Care Med Exp 2019;7:67. [PMID: 31802303 PMCID: PMC6892994 DOI: 10.1186/s40635-019-0282-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/13/2019] [Indexed: 12/28/2022] Open

Abstract

Background

Damage control resuscitation (DCR) and damage control surgery (DCS) is the main strategy in patients with uncontrollable hemorrhagic shock. One aspect of DCR is permissive hypotension. However, the duration of hypotension that can be tolerated without affecting the brain is unknown. In the present study we investigate the effect of 60 min severe hypotension on the brain’s energy metabolism and seek to verify earlier findings that venous cerebral blood can be used as a marker of global cerebral energy state.

Material and methods

Ten pigs were anaesthetized, and vital parameters recorded. Microdialysis catheters were placed in the left parietal lobe, femoral artery, and superior sagittal sinus for analysis of lactate, pyruvate, glucose, glycerol, and glutamate. Hemorrhagic shock was induced by bleeding the animal until mean arterial pressure (MAP) of 40 mmHg was achieved. After 60 min the pigs were resuscitated with autologous blood and observed for 3 h.

Results

At baseline the lactate to pyruvate ratios (LP ratio) in the hemisphere, artery, and sagittal sinus were (median (interquartile range)) 13 (8–16), 21 (18–24), and 9 (6–22), respectively. After induction of hemorrhagic shock, the LP ratio from the left hemisphere in 9 pigs increased to levels indicating a reversible perturbation of cerebral energy metabolism 19 (12–30). The same pattern was seen in LP measurements from the femoral artery 28 (20–35) and sagittal sinus 22 (19–26). At the end of the experiment hemisphere, artery and sinus LP ratios were 16 (10–23), 17 (15–25), and 17 (10–27), respectively. Although hemisphere and sinus LP ratios decreased, they did not reach baseline levels (p < 0.05). In one pig hemisphere LP ratio increased to a level indicating irreversible metabolic perturbation (LP ratio > 200).

Conclusion

During 60 min of severe hypotension intracerebral microdialysis shows signs of perturbations of cerebral energy metabolism, and these changes trend towards baseline values after resuscitation. Sagittal sinus microdialysis values followed hemisphere values but were not distinguishable from systemic arterial values. Venous (jugular bulb) microdialysis might have a place in monitoring conditions where global cerebral ischemia is a risk.

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Janata A, Magnet IAM, Schreiber KL, Wilson CD, Stezoski JP, Janesko-Feldman K, Kochanek PM, Drabek T. Minocycline fails to improve neurologic and histologic outcome after ventricular fibrillation cardiac arrest in rats. World J Crit Care Med 2019;8:106-119. [PMID: 31853446 PMCID: PMC6918046 DOI: 10.5492/wjccm.v8.i7.106] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 09/17/2019] [Accepted: 10/27/2019] [Indexed: 02/06/2023] Open

Abstract

BACKGROUND

Prolonged cardiac arrest (CA) produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities. Among other potential mechanisms, microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults. Minocycline is neuroprotective in some brain ischemia models, either by blunting the microglial response or by a direct effect on neurons.

AIM

To improve survival, attenuate neurologic deficits, neuroinflammation, and histological damage after ventricular fibrillation (VF) CA in rats.

METHODS

Adult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression, epinephrine, bicarbonate, and defibrillation. After return of spontaneous circulation (ROSC), rats were randomized to two groups: (1) Minocycline 90 mg/kg intraperitoneally (i.p.) at 15 min ROSC, followed by 22.5 mg/kg i.p. every 12 h for 72 h; and (2) Controls, receiving the same volume of vehicle (phosphate-buffered saline). The rats were kept normothermic during the postoperative course. Neurologic injury was assessed daily using Overall Performance Category (OPC; 1 = normal, 5 = dead) and Neurologic Deficit Score (NDS; 0% = normal, 100% = dead). Rats were sacrificed at 72 h. Neuronal degeneration (Fluoro-Jade C staining) and microglia proliferation (anti-Iba-1 staining) were quantified in four selectively vulnerable brain regions (hippocampus, striatum, cerebellum, cortex) by three independent reviewers masked to the group assignment.

RESULTS

In the minocycline group, 8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group (P = 0.46). The degree of neurologic deficit at 72 h [median, (interquartile range)] was not different between survivors in minocycline vs controls: OPC 1.5 (1-2.75) vs 2 (1.25-3), P = 0.442; NDS 12 (2-20) vs 17 (7-51), P = 0.328) or between all studied rats. The number of degenerating neurons (minocycline vs controls, mean ± SEM: Hippocampus 58 ± 8 vs 76 ± 8; striatum 121 ± 43 vs 153 ± 32; cerebellum 20 ± 7 vs 22 ± 8; cortex 0 ± 0 vs 0 ± 0) or proliferating microglia (hippocampus 157 ± 15 vs 193 cortex 0 ± 0 vs 0 ± 0; 16; striatum 150 ± 22 vs 161 ± 23; cerebellum 20 ± 7 vs 22 ± 8; cortex 26 ± 6 vs 31 ± 7) was not different between groups in any region (all P > 0.05). Numerically, there were approximately 20% less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group, with a consistent pattern of histological damage across the individual regions of interest.

CONCLUSION

Minocycline did not improve survival and failed to confer substantial benefits on neurologic function, neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.

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Affiliation(s)

Andreas Janata Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States Emergency Department, KA Rudolfstiftung, Vienna 1030, Austria
Ingrid AM Magnet Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Department of Emergency Medicine, Vienna General Hospital, Medical University of Vienna, Vienna 1090, Austria
Kristin L Schreiber Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
Caleb D Wilson Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Wyoming Otolaryngology, Wyoming Medical Center, Casper, WY 82604, United States
Jason P Stezoski Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
Keri Janesko-Feldman Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
Patrick M Kochanek Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
Tomas Drabek Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, United States Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States

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Mihara R, Takasu A, Maemura K, Minami T. Prolonged severe hemorrhagic shock at a mean arterial pressure of 40 mmHg does not lead to brain damage in rats. Acute Med Surg 2018;5:350-357. [PMID: 30338081 PMCID: PMC6167391 DOI: 10.1002/ams2.361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 06/24/2018] [Indexed: 11/17/2022] Open

Treatment of combined traumatic brain injury and hemorrhagic shock with fractionated blood products versus fresh whole blood in a rat model. Eur J Trauma Emerg Surg 2018;45:263-271. [PMID: 29344708 DOI: 10.1007/s00068-018-0908-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 01/12/2018] [Indexed: 10/18/2022]

Abstract

INTRODUCTION

Treatment of combined traumatic brain injury and hemorrhagic shock, poses a particular challenge due to the possible conflicting consequences. While restoring diminished volume is the treatment goal for hypovolemia, maintaining adequate cerebral perfusion pressure and avoidance of secondary damage remains a treatment goal for the injured brain. Various treatment modalities have been proposed, but the optimal resuscitation fluid and goals have not yet been clearly defined. A growing body of evidence suggests that in hypovolemic shock, resuscitation with fresh whole blood (FWB) may be superior to component therapy without platelets (which are likely to be unavailable in the pre-hospital setting). Nevertheless, the effects of this approach have not been studied in the combined injury. Previously, in a rat model of combined injury we have found that mild resuscitation to MABP of 80 mmHg with FWB is superior to fluid resuscitation or aggressive resuscitation with FWB. In this study, we investigate the physiological and neurological outcomes in a rat model of combined traumatic brain injury (TBI) and hypovolemic shock, submitted to treatment with varying amounts of FWB, compared to similar resuscitation goals with fractionated blood products-red blood cells (RBCs) and plasma in a 1:1 ratio regimen.

MATERIALS AND METHODS

40 male Lewis rats were divided into control and treatment groups. TBI was inflicted by a free-falling rod on the exposed cranium. Hypovolemia was induced by controlled hemorrhage of 30% blood volume. Treatment groups were treated either with fresh whole blood or with RBC + plasma in a 1:1 ratio, achieving a resuscitation goal of a mean arterial blood pressure (MAP) of 80 mmHg at 15 min. MAP was assessed at 60 min, and neurological outcomes and mortality in the subsequent 24 h.

RESULTS

At 60 min, hemodynamic parameters were improved compared to controls, but not significantly different between treatment groups. Survival rates at 48 h were 100% for both of the mildly resuscitated groups (MABP 80 mmHg) with FWB and RBC + plasma. The best neurological outcomes were found in the group mildly resuscitated with FWB and were better when compared to resuscitation with RBC + plasma to the same MABP goal (FWB: Neurological Severity Score (NSS) 6 ± 2, RBC + plasma: NSS 10 ± 2, p = 0.02).

CONCLUSIONS

In this study, we find that mild resuscitation with goals of restoring MAP to 80 mmHg (which is lower than baseline) with FWB, provided better hemodynamic stability and survival. However, the best neurological outcomes were found in the group resuscitated with FWB. Thus, we suggest that resuscitation with FWB is a feasible modality in the combined TBI + hypovolemic shock scenario, and may result in improved outcomes compared to platelet-free component blood products.

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Nora GJ, Harun R, Fine DF, Hutchison D, Grobart AC, Stezoski JP, Munoz MJ, Kochanek PM, Leak RK, Drabek T, Wagner AK. Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment. J Neurochem 2017;142:305-322. [PMID: 28445595 DOI: 10.1111/jnc.14058] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 04/19/2017] [Accepted: 04/20/2017] [Indexed: 01/21/2023]

Abstract

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal electrical stimulations (60Hz, 10s) in rats to characterize presynaptic components of DA neurotransmission in the dorsal striatum (D-Str) and nucleus accumbens 14 days after a 5-min VF-CA when compared to Sham or Naïve. VF-CA increased D-Str-evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (Vmax ). Methylphenidate (10 mg/kg), a DA transporter inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60 Hz, 5 s stimulation response. Methylphenidate increased initial evoked overflow [DA] more-so in VF-CA versus Sham and reduced D-Str Vmax in VF-CA but not Shams; these findings are consistent with upregulated striatal DA transporter in VF-CA versus Sham. Our work demonstrates that 5-min VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions.

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Affiliation(s)

Gerald J Nora Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Rashed Harun Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
David F Fine Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Daniel Hutchison Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, USA
Adam C Grobart Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Jason P Stezoski Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Miranda J Munoz Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Patrick M Kochanek Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Rehana K Leak Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, USA
Tomas Drabek Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Amy K Wagner Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

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Karmacharya MB, Kim KH, Kim SY, Chung J, Min BH, Park SR, Choi BH. Low intensity ultrasound inhibits brain oedema formation in rats: potential action on AQP4 membrane localization. Neuropathol Appl Neurobiol 2016;41:e80-94. [PMID: 25201550 DOI: 10.1111/nan.12182] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 09/03/2014] [Indexed: 12/23/2022]

Simon DW, Vagni VM, Kochanek PM, Clark RSB. Combined Neurotrauma Models: Experimental Models Combining Traumatic Brain Injury and Secondary Insults. Methods Mol Biol 2016;1462:393-411. [PMID: 27604730 DOI: 10.1007/978-1-4939-3816-2_22] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]

Palmer L, Martin L. Traumatic coagulopathy--part 2: Resuscitative strategies. J Vet Emerg Crit Care (San Antonio) 2014;24:75-92. [PMID: 24393363 DOI: 10.1111/vec.12138] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 11/10/2013] [Indexed: 11/26/2022]

Abstract

OBJECTIVE

To discuss the current resuscitative strategies for trauma-induced hemorrhagic shock and acute traumatic coagulopathy (ATC).

ETIOLOGY

Hemorrhagic shock can be acutely fatal if not immediately and appropriately treated. The primary tenets of hemorrhagic shock resuscitation are to arrest hemorrhage and restore the effective circulating volume. Large volumes of isotonic crystalloids have been the resuscitative strategy of choice; however, data from experimental animal models and retrospective human analyses now recognize that large-volume fluid resuscitation in uncontrolled hemorrhage may be deleterious. The optimal resuscitative strategy has yet to be defined. In human trauma, implementing damage control resuscitation with damage control surgery for controlling ongoing hemorrhage, acidosis, and hypothermia; managing ATC; and restoring effective circulating volume is emerging as a more optimal resuscitative strategy. With hyperfibrinolysis playing an integral role in the manifestation of ATC, the use of antifibrinolytics (eg, tranexamic acid and aminocaproic acid) may also serve a beneficial role in the early posttraumatic period. Considering the sparse information regarding these resuscitative techniques in veterinary medicine, veterinarians are left with extrapolating information from human trials and experimental animal models.

DIAGNOSIS

Viscoelastic tests integrated with predictive scoring systems may prove to be the most reliable methods for early detection of ATC as well as for guiding transfusion requirements.

SUMMARY

Hemorrhage accounts for up to 40% of human trauma-related deaths and remains the leading cause of preventable death in human trauma. The exact proportion of trauma-related deaths due to exsanguinations in veterinary patients remains uncertain. Survivability depends upon achieving rapid definitive hemostasis, early attenuation of posttraumatic coagulopathy, and timely restoration of effective circulating volume. Early institution of damage control resuscitation in severely injured patients with uncontrolled hemorrhage has the ability to curtail posttraumatic coagulopathy and the exacerbation of metabolic acidosis and hypothermia and improve survival until definitive hemostasis is achieved.

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Yeung PKK, Shen J, Chung SSM, Chung SK. Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage. BMC Neurosci 2013;14:131. [PMID: 24156724 PMCID: PMC3815232 DOI: 10.1186/1471-2202-14-131] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 10/15/2013] [Indexed: 01/15/2023] Open

Abstract

Background

Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over-expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis.

Results

The GET-1 mice experienced a higher mortality rate and significantly more severe neurological deficits, blood–brain barrier breakdown and vasogenic edema compared to the non-transgenic (Ntg) mice following SAH. Oral administration of vasopressin V_1a receptor antagonist, SR 49059, significantly reduced the cerebral water content in the GET-1 mice. Furthermore, the GET-1 mice showed significantly more pronounced middle cerebral arterial (MCA) constriction after SAH. Immunocytochemical analysis showed that the calcium-activated potassium channels and the phospho-eNOS were significantly downregulated, whereas PKC-α expression was significantly upregulated in the MCA of the GET-1 mice when compared to Ntg mice after SAH. Administration of ABT-627 (ET_A receptor antagonist) significantly down-regulated PKC-α expression in the MCA of the GET-1 mice following SAH.

Conclusions

The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ET_A receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ET_A receptor antagonist) and SR 49059 (vasopressin V_1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.

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MRI assessment of cerebral blood flow after experimental traumatic brain injury combined with hemorrhagic shock in mice. J Cereb Blood Flow Metab 2013;33:129-36. [PMID: 23072750 PMCID: PMC3597358 DOI: 10.1038/jcbfm.2012.145] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]

Hemerka JN, Wu X, Dixon CE, Garman RH, Exo JL, Shellington DK, Blasiole B, Vagni VA, Janesko-Feldman K, Xu M, Wisniewski SR, Bayır H, Jenkins LW, Clark RSB, Tisherman SA, Kochanek PM. Severe brief pressure-controlled hemorrhagic shock after traumatic brain injury exacerbates functional deficits and long-term neuropathological damage in mice. J Neurotrauma 2012;29:2192-208. [PMID: 22738159 DOI: 10.1089/neu.2011.2303] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open

Abstract

Hypotension after traumatic brain injury (TBI) worsens outcome. We published the first report of TBI plus hemorrhagic shock (HS) in mice using a volume-controlled approach and noted increased neuronal death. To rigorously control blood pressure during HS, a pressure-controlled HS model is required. Our hypothesis was that a brief, severe period of pressure-controlled HS after TBI in mice will exacerbate functional deficits and neuropathology versus TBI or HS alone. C57BL6 male mice were randomized into four groups (n=10/group): sham, HS, controlled cortical impact (CCI), and CCI+HS. We used a pressure-controlled shock phase (mean arterial pressure [MAP]=25-27 mm Hg for 35 min) and its treatment after mild to moderate CCI including, a 90 min pre-hospital phase, during which lactated Ringer's solution was given to maintain MAP >70 mm Hg, and a hospital phase, when the shed blood was re-infused. On days 14-20, the mice were evaluated in the Morris water maze (MWM, hidden platform paradigm). On day 21, the lesion and hemispheric volumes were quantified. Neuropathology and hippocampal neuron counts (hematoxylin and eosin [H&E], Fluoro-Jade B, and NeuN) were evaluated in the mice (n=60) at 24 h, 7 days, or 21 days (n=5/group/time point). HS reduced MAP during the shock phase in the HS and CCI+HS groups (p<0.05). Fluid requirements during the pre-hospital phase were greatest in the CCI+HS group (p<0.05), and were increased in HS versus sham and CCI animals (p<0.05). MWM latency was increased on days 14 and 15 after CCI+HS (p<0.05). Swim speed and visible platform latency were impaired in the CCI+HS group (p<0.05). CCI+HS animals had increased contusion volume versus the CCI group (p<0.05). Hemispheric volume loss was increased 33.3% in the CCI+HS versus CCI group (p<0.05). CA1 cell loss was seen in CCI+HS and CCI animals at 24 h and 7 days (p<0.05). CA3 cell loss was seen after CCI+HS (p<0.05 at 24 h and 7 days). CA1 cell loss at 21 days was seen only in CCI+HS animals (p<0.05). Brief, severe, pressure-controlled HS after CCI produces robust functional deficits and exacerbates neuropathology versus CCI or HS alone.

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Navarro JC, Pillai S, Cherian L, Garcia R, Grill RJ, Robertson CS. Histopathological and behavioral effects of immediate and delayed hemorrhagic shock after mild traumatic brain injury in rats. J Neurotrauma 2012;29:322-34. [PMID: 22077317 DOI: 10.1089/neu.2011.1979] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open

Abstract

The purpose of this study was to investigate the increased susceptibility of the brain, after a controlled mild cortical impact injury, to a secondary ischemic insult. The effects of the duration and the timing of the secondary insult after the initial cortical injury were studied. Rats anesthetized with isoflurane underwent a 3 m/sec, 2.5-mm deformation cortical impact injury followed by hypotension to 40 mm Hg induced by withdrawing blood from a femoral vein. The duration of hypotension was varied from 40 to 60 min. The timing of 60 min of hypotension was varied from immediately post-injury to 7 days after the injury. Outcome was assessed by behavioral tasks and histological examination at 2 weeks post-injury. A separate group of animals underwent measurement of the acute physiology including mean blood pressure (MAP), intracranial pressure (ICP), and cerebral blood flow (CBF) using a laser Doppler technique. Increasing durations of hypotension resulted in marked expansion of the contusion, from 6.5±1.8 mm³ with sham hypotension to 27.1±3.9 mm³ with 60 min of hypotension. This worsening of the contusion was found only when then hypotension occurred immediately after injury or at 1 h after injury. CA3 neuron loss followed a similar pattern, but the injury group differences were not significant. Motor tasks, including beam balance and beam walking, were significantly worse following 50 and 60 min of hypotension. Performance on the Morris water maze task was also significantly related to the injury group. Studies of the acute cerebral hemodynamics demonstrated that CBF was significantly more impaired during hypotension in the animals that underwent the mild TBI compared to those that underwent sham TBI. The perfusion deficit was worst at the impact site, but also significant in the pericontusional brain. With 50 and 60 min of hypotension, CBF did not recover following resuscitation at the impact site, and recovered only transiently in the pericontusional brain. These results demonstrate that mild TBI, like more severe levels of TBI, can impair the brain's ability to maintain CBF during a period of hypotension, and result in a worse outcome.

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Intravenous fluid resuscitation for the trauma patient. Curr Opin Crit Care 2011;16:283-8. [PMID: 20601865 DOI: 10.1097/mcc.0b013e32833bf774] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]

Geoghegan J, Dennis A, Manji M. Hypotensive resuscitation. TRAUMA-ENGLAND 2010. [DOI: 10.1177/1460408610368743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]

Is cerebral microcirculation really preserved in shock states?*. Crit Care Med 2010;38:1008-9. [DOI: 10.1097/ccm.0b013e3181d16958] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]

Targeted overexpression of endothelin-1 in astrocytes leads to more severe cytotoxic brain edema and higher mortality. J Cereb Blood Flow Metab 2009;29:1891-902. [PMID: 19707218 DOI: 10.1038/jcbfm.2009.175] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]

Han F, Boller M, Guo W, Merchant RM, Lampe JW, Smith TM, Becker LB. A rodent model of emergency cardiopulmonary bypass resuscitation with different temperatures after asphyxial cardiac arrest. Resuscitation 2009;81:93-9. [PMID: 19926192 DOI: 10.1016/j.resuscitation.2009.09.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2009] [Revised: 08/24/2009] [Accepted: 09/18/2009] [Indexed: 01/09/2023]

Dennis AM, Haselkorn ML, Vagni VA, Garman RH, Janesko-Feldman K, Bayir H, Clark RSB, Jenkins LW, Dixon CE, Kochanek PM. Hemorrhagic shock after experimental traumatic brain injury in mice: effect on neuronal death. J Neurotrauma 2009;26:889-99. [PMID: 18781889 DOI: 10.1089/neu.2008.0512] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open

Preserved cerebral microcirculation during cardiogenic shock. Crit Care Med 2009;37:2333-7. [PMID: 19487927 DOI: 10.1097/ccm.0b013e3181a3a97b] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]

Abstract

OBJECTIVE

To hypothesize that in severe states of cardiogenic shock with profound decreases in buccal microcirculation, the cerebral microcirculation may be selectively protected. Decreases in buccal microcirculatory flow are closely associated with the severity and outcomes of circulatory shock.

DESIGN

We investigated the concurrent changes in cerebral and buccal microcirculation, in a rat model of cardiogenic shock caused by left ventricular failure.

DESIGN

Randomized prospective animal study.

SETTING

University-affiliated animal research laboratory.

SUBJECTS

Sprague-Dawley rats.

INTERVENTIONS

Studies were performed in ten male Sprague-Dawley rats, weighing between 450 and 550 g. After intraperitonial pentobarbital anesthesia and tracheostomy, a craniotomy exposed the parietal cortex for visualization of microcirculation. Animals then underwent thoracotomy and banding of ascending aorta producing left ventricular failure and cardiogenic shock.

MEASUREMENTS AND MAIN RESULTS

Over a 4-hr interval, effects on arterial pressure, cardiac output, left ventricular end-diastolic volume, and ejection fractions were measured. The cerebral and buccal microcirculations were visualized concurrently with the aid of orthogonal polarization spectral imaging. Animals were randomized to identically treated controls in which the aorta was not ligated. Mean arterial pressure, cardiac output, and ejection fraction decreased strikingly and end-diastolic left ventricular volume more than doubled within 30 mins after aortic banding. The buccal microcirculation was concurrently reduced. However, cerebral microcirculatory flow was fully preserved.

CONCLUSIONS

In contrast to striking reduction in cardiac output and arterial pressures together with buccal microcirculatory flow, cerebral cortical microcirculatory flow was fully preserved during cardiogenic shock. These findings further document a dissociation between the systemic and cerebral circulations and potentially explain earlier clinical and experimental observations that the brain is selectively protected during severe states of cardiogenic shock in the absence of cardiac arrest.

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Deniz T, Agalar C, Ozdogan M, Edremitlioglu M, Eryilmaz M, Devay SD, Deveci O, Agalar F. Mild Hypothermia Improves Survival During Hemorrhagic Shock Without Affecting Bacterial Translocation. J INVEST SURG 2009;22:22-8. [DOI: 10.1080/08941930802566706] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]

Preoperative resuscitation of the trauma patient. Curr Opin Anaesthesiol 2008;21:216-21. [PMID: 18443492 DOI: 10.1097/aco.0b013e3282f60a46] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]

Yang R, Tan X, Kenney RJ, Thomas A, Landis M, Qureshi N, Morrison DC, Van Way CW. Hemorrhagic Shock in the Rat: Comparison of Carotid and Femoral Cannulation. J Surg Res 2008;144:124-6. [PMID: 17560609 DOI: 10.1016/j.jss.2007.04.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2006] [Revised: 03/28/2007] [Accepted: 04/05/2007] [Indexed: 11/20/2022]

Drabek T, Fisk JA, Dixon CE, Garman RH, Stezoski J, Wisnewski SR, Wu X, Tisherman SA, Kochanek PM. Prolonged deep hypothermic circulatory arrest in rats can be achieved without cognitive deficits. Life Sci 2007;81:543-552. [PMID: 17658556 DOI: 10.1016/j.lfs.2007.06.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 06/11/2007] [Accepted: 06/16/2007] [Indexed: 02/07/2023]

Kentner R, Safar P, Behringer W, Wu X, Henchir J, Ma L, Hsia CJC, Tisherman SA. Small volume resuscitation with tempol is detrimental during uncontrolled hemorrhagic shock in rats. Resuscitation 2007;72:295-305. [PMID: 17112648 DOI: 10.1016/j.resuscitation.2006.05.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2005] [Revised: 05/26/2006] [Accepted: 05/26/2006] [Indexed: 10/23/2022]

Abstract

BACKGROUND

In a previous study, titration of a hypertonic saline (HTS) solution during severe uncontrolled hemorrhagic shock (UHS) failed to reduce mortality. In a separate study, a novel antioxidant, polynitroxylated albumin (PNA) plus tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), infused during shock increased long-term survival. We hypothesized that combining potent antioxidants with a hypertonic solution during UHS would preserve the logistical advantage of small volume resuscitation and improve survival.

METHODS

An UHS outcome model in rats was used. UHS phase I (90 min) included blood withdrawal of 30 ml/kg over 15 min, followed by tail amputation for uncontrolled bleeding. At 20 min, rats were randomized to four groups (n=10 each) for hypotensive resuscitation from 20 to 90 min (mean arterial pressure [MAP] > or = 40 mmHg): HTS/starch group received 7.2% NaCl/10% hydroxyethyl starch; HTS/albumin group received 7.5% NaCl/20% albumin; HTS/PNA group received 7.5% NaCl/20% PNA; HTS/albumin+tempol group received 7.5% NaCl/20% albumin plus tempol. Resuscitation phase II (180 min) included hemostasis, return of shed blood and administration of fluids to restore MAP > or = 80 mmHg. Observation phase III was to 72 h.

RESULTS

The total amount of fluid required to maintain hypotensive MAP during HS was low and did not differ between groups (range: 3.4+/-1.9 to 5.3+/-2.5 ml/kg). The rate of fluid administration required was higher in the HTS/albumin+tempol group compared to all other groups (p=0.006). Additional uncontrolled blood loss was highest in the HTS/PNA group (16.2+/-5.7 ml/kg [p=0.01] versus 10.4+/-7.9 ml/kg in the HTS/starch group, 7.7+/-5.2 ml/kg in the HTS/albumin group and 8.2+/-7.1 ml/kg in the HTS/albumin+tempol group). MAP after start of resuscitation in phase I was lower in the HTS/albumin+tempol group than the HTS/albumin or HTS/PNA groups (p<0.01). This group was also less tachycardic. Long-term survival was low in all groups (2 of 10 after HTS/starch and 1 of 10 after HTS/albumin, 3 of 10 after HTS/PNA, 1 of 10 after HTS/albumin+tempol). Median survival time was shortest in the HTS/albumin+tempol group (72 min [CI 34-190]) compared to all other groups (p=0.01).

CONCLUSIONS

Despite its benefits in other model systems, free tempol is potentially hazardous when combined with hypertonic fluids. PNA abrogates these deleterious effects on acute mortality but may lead to increased blood loss in the setting of UHS.

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Wu X, Drabek T, Kochanek PM, Henchir J, Stezoski SW, Stezoski J, Cochran K, Garman R, Tisherman SA. Induction of profound hypothermia for emergency preservation and resuscitation allows intact survival after cardiac arrest resulting from prolonged lethal hemorrhage and trauma in dogs. Circulation 2006;113:1974-1982. [PMID: 16618818 DOI: 10.1161/circulationaha.105.587204] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]

Lin T, Koustova E, Chen H, Rhee PM, Kirkpatrick J, Alam HB. Energy Substrate-Supplemented Resuscitation Affects Brain Monocarboxylate Transporter Levels and Gliosis in a Rat Model of Hemorrhagic Shock. ACTA ACUST UNITED AC 2005;59:1191-202; discussion 1202. [PMID: 16385299 DOI: 10.1097/01.ta.0000188646.86995.9d] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]

Abstract

BACKGROUND

Monocarboxylate (MC)-supplemented resuscitation has been shown to attenuate cellular injury after hemorrhagic shock. However, little is known about its effect on the central nervous system. The brain can use MCs such as lactate, pyruvate, and beta-hydroxybutyrate as energy substrates. The transit of MCs into the central nervous system is facilitated by the monocarboxylate transporters (MCTs), and their blockage can exacerbate neuronal damage. We examined the expression of MCT1 and markers specific for activation of astroglia and microglia in the brains of rats subjected to hemorrhagic shock and resuscitation. The hypothesis was that resuscitation with MC-based fluids would be accompanied by MCT1 up-regulation and glial response.

METHODS

Rats (n = 30) were subjected to volume-controlled hemorrhage. Test groups included: sham, no resuscitation, resuscitation with normal saline, resuscitation with racemic lactated Ringer's solution, resuscitation with pyruvate Ringer's solution, and resuscitation with beta-hydroxybutyrate-containing ketone Ringer's solution. Plasma levels of MC were measured serially. The brains were investigated using GFAP, CD11b, CD43, MCT1, and GLUT1 immunohistochemistry.

RESULTS

Rats resuscitated with MC-containing fluids had increased levels of MCT1 in brain endothelial cells and neuropil compared with sham rats. Enhanced staining was localized to the choroid plexus, astrocytic end feet, and white matter structures. None of the resuscitation treatment induced astrocytic hyperplasia, and pyruvate Ringer's solution and ketone Ringer's solution resuscitation led to hypertrophy of astrocytes.

CONCLUSION

In hemorrhagic shock, resuscitation with MC-based fluids increased brain MCT1 level and led to activation of astrocytes. Enhanced MC trafficking could be an essential route for energy supply to neurons under adverse circulatory conditions.

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Daull P, Blouin A, Cayer J, Beaudoin M, Belleville K, Sirois P, Nantel F, Chang TMS, Battistini B. Profiling biochemical and hemodynamic markers using chronically instrumented, conscious and unrestrained rats undergoing severe, acute controlled hemorrhagic hypovolemic shock as an integrated in-vivo model system to assess new blood substitutes. Vascul Pharmacol 2005;43:289-301. [PMID: 16253569 DOI: 10.1016/j.vph.2005.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2005] [Accepted: 09/05/2005] [Indexed: 10/25/2022]

Abstract

The aim of the present study was to assess several biochemical and physiological endpoint parameters alongside controlled hemorrhagic and recovery phases of chronically instrumented, conscious and unrestrained healthy rats. Male Sprague-Dawley rats (12-14 weeks; 430+/-20 g; n=22-18) were instrumented with a saline-perfused femoral arterial catheter and placed individually in a metabolic cage for up to 20 days, allowing instant assessments of the hemodynamic profile and blood and urine sampling for hematological profile and biochemical measurements to assess hepatic, renal and metabolic functions. In addition, body weight, food and water intake, and diuresis were monitored daily. After a 7-day stabilization period, the rats underwent severe and acute hemorrhagic shock (HS) (removal of 50% of total circulating blood volume), kept in hypovolemic shock for an ischemic period of 50 min and then resuscitated over 10 min. Gr. 1 was re-infused with autologous shed blood (AB; n=10) whereas Gr. 2 was infused 1:1 with a solution of sterile saline-albumin (SA; 7% w/v) (n=8-12). Ischemic rats recovered much more rapidly following AB re-infusion than those receiving SA. Normal hemodynamic and biochemical profiles were re-established after 24 h. Depressed blood pressure lasted 4-5 days in SA rats. The hematological profile in the SA resuscitated rats was even more drastically affected. Circulating plasma concentrations of hemoglobin (-40%), hematocrit (-50%), RBC (-40%) and platelets (-41%) counts were still severely decreased 24 h after the acute ischemic event whereas WBC counts increased 2.2-fold by day 4. It took 5-9 days for these profiles to normalize after ischemia-reperfusion with SA. Diuresis increased in both groups (by 45+/-7% on day 1) but presented distinct electrolytic profiles. Hepatic and renal functions were normal in AB rats whereas altered in SA rats. The present set of experiments enabled us to validate a model of HS in conscious rats and the use of an integrated in vivo platform as a valuable tool to characterize HS-induced stress and to test new classes of blood substitutes in real time, post-event, over days.

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Kentner R, Safar P, Prueckner S, Behringer W, Wu X, Henchir J, Ruemelin A, Tisherman SA. Titrated hypertonic/hyperoncotic solution for hypotensive fluid resuscitation during uncontrolled hemorrhagic shock in rats. Resuscitation 2005;65:87-95. [PMID: 15797280 DOI: 10.1016/j.resuscitation.2004.10.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2002] [Revised: 10/19/2004] [Accepted: 10/19/2004] [Indexed: 11/23/2022]

Abstract

BACKGROUND

In volume- or pressure-controlled hemorrhagic shock (HS) a bolus intravenous infusion of hypertonic/hyperoncotic solution (HHS) proved beneficial compared to isotonic crystalloid solutions. During uncontrolled HS in animals, however, HHS by bolus increased blood pressure unpredictably, and increased blood loss and mortality. We hypothesized that a titrated i.v. infusion of HHS, compared to titrated lactated Ringer's solution (LR), for hypotensive fluid resuscitation during uncontrolled HS reduces fluid requirement, does not increase blood loss, and improves survival.

METHODS

We used our three-phased uncontrolled HS outcome model in rats. HS phase I began with blood withdrawal of 3 ml/100g over 15 min, followed by tail amputation. Then, hydroxyethyl starch 10% in NaCl 7.2% was given i.v. to the HHS group (n=10) and LR to the control group (n=10), both titrated to prevent mean arterial pressure (MAP) from falling below 40 mmHg during HS time 20-90 min. At HS 90 min, resuscitation phase II of 180 min began with hemostasis, return of all the blood initially shed, plus fluids i.v. as needed to maintain normotension (MAP>or=70 mmHg). Liver dysoxia was monitored as increase in liver surface pCO2 during phases I and II. Observation phase III was to 72 h.

RESULTS

During HS, preventing a decrease in MAP below 40 mmHg required HHS 4.9+/-0.6 ml/kg (all data mean+/-S.E.M.), compared to LR 62.2+/-16.6 ml/kg (P<0.001), with no group difference in MAP. Uncontrolled blood loss during HS from the tail stump was 13.3+/-1.9 ml/kg with HHS infusion, versus 12.6+/-2.5 ml/kg with LR infusion (P=0.73). Serum sodium concentrations were moderately elevated at the end of HS in the HHS group (149+/-3 mmol/l) versus the LR group (139+/-1 mmol/l) (P=0.001), and remained elevated throughout. Liver pCO2 increased during HS in both groups equally (P<0.001 versus baseline), and tended to return to baseline levels at the end of HS. Blood gas and lactate values throughout did not differ between groups. During HS, 2 of 10 rats in the HHS group versus 0 of 10 in the LR group died (P=0.47). There was no difference between HHS and LR groups in survival rates to 72 h (3 of 10 in the HHS group versus 2 of 10 in the LR group) (P=1.0). Survival times, by life table analysis, were not different (P=0.75).

CONCLUSION

In prolonged uncontrolled HS, a titrated i.v. infusion of HHS can maintain controlled hypotension with only one-tenth of the volume of LR required, without increasing blood loss. This titrated HHS strategy may not increase the chance of long-term survival.

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Jonas RA. The effect of extracorporeal life support on the brain: cardiopulmonary bypass. Semin Perinatol 2005;29:51-7. [PMID: 15921153 DOI: 10.1053/j.semperi.2005.02.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]

Hachimi-Idrissi S, Yang X, Nguyen DN, Huyghens L. Combination of therapeutic mild hypothermia and delayed fluid resuscitation improved survival after uncontrolled haemorrhagic shock in mechanically ventilated rats. Resuscitation 2004;62:303-10. [PMID: 15325450 DOI: 10.1016/j.resuscitation.2004.04.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2004] [Revised: 03/22/2004] [Accepted: 04/04/2004] [Indexed: 10/26/2022]

Miyake M, Grinberg OY, Hou H, Steffen RP, Elkadi H, Swartz HM. The Effect of RSR13, a Synthetic Allosteric Modifier of Hemoglobin, on Brain Tissue pO2 (Measured by Eproximetry) Following Severe Hemorrhagic Shock in Rats. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003;530:319-29. [PMID: 14562728 DOI: 10.1007/978-1-4615-0075-9_30] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]

Fowler R, Pepe PE. Prehospital care of the patient with major trauma. Emerg Med Clin North Am 2002;20:953-74. [PMID: 12476889 DOI: 10.1016/s0733-8627(02)00038-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]

Abstract

Recent research efforts have demonstrated that many longstanding practices for the prehospital resuscitation of trauma patients may be inappropriate under certain circumstances. For example, traditional practices, such as application of anti-shock garments and i.v. fluid administration to raise blood pressure, may even be detrimental in certain patients with uncontrolled bleeding, particularly those with penetrating injuries. ETI, although potentially capable of transiently prolonging a patient's ability to tolerate circulatory arrest, may also be harmful if overzealous PPV further compromises cardiac output, particularly in those patients with severe hemodynamic instability. In addition, if these procedures delay patient transport, any benefit that they may offer could be outweighed by the delay in definitive care. Although traditionally taught to "hyperventilate" the patient with severe head injury, current recommendations are to avoid this tactic unless there is evidence of herniation. Even time-honored traditions, such as universal spinal precautions and CPR during circulatory arrest, are being scrutinized [2,134]. Further prospective randomized clinical trials are needed to better define the role of many overlapping therapies in prehospital trauma care. Such research must specifically address and stratify the different mechanisms of injury, anatomic areas involved, and the physiologic staging of the injury. Furthermore, the efficacy of a single intervention may be masked by a confounding variable [5]. For example, a trial of an effective new HBOC in moribund patients that indicates no advantage in the study results may have been confounded by overzealous PPV, which may have led to suboptimal outcomes. It is hoped that, in the future, EMS physicians will be able to not only better discriminate in their management of patients with major trauma but also improve outcomes as a result.

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Fowler R, Pepe PE. Fluid resuscitation of the patient with major trauma. Curr Opin Anaesthesiol 2002;15:173-8. [PMID: 17019198 DOI: 10.1097/00001503-200204000-00006] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]

Leonov Y, Safar P, Sterz F, Stezoski SW. Extending the golden hour of hemorrhagic shock tolerance with oxygen plus hypothermia in awake rats. An exploratory study. Resuscitation 2002;52:193-202. [PMID: 11841888 DOI: 10.1016/s0300-9572(01)00453-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]

Abstract

In a previous study of volume-controlled hemorrhagic shock (HS) in awake rats, without fluid resuscitation, either breathing of 100% oxygen or moderate hypothermia while breathing air, increased survival time. We hypothesized that combining oxygen and hypothermia can maximally extend the "golden hour" of HS from which resuscitation can be successful in terms of survival rate. Rats were prepared under light general anesthesia, breathing spontaneously via face mask, and then awakened for 2 h. Then, 3.25 ml arterial blood/100 g were withdrawn over 20 min. At the end of HS of 30, 60, 90 or 180 min duration, the shed blood was reinfused. Breathing was spontaneous. Survival endpoint was 24 h or earlier death. HS of 30 or 60 min was used for preliminary experiments; HS of 90 or 180 min for 35 definitive experiments. Control groups A-1 and B-1 had normothermia (rectal temperature 37.5 degrees C) and were breathing air. Treatment groups A-2 and B-2 had total body surface cooling during HS to rectal temperature 32 degrees C and were breathing 100% O(2). Arterial pressure during HS was higher in the hypothermia-O(2) groups. With HS of 90 min, in the normothermia-air group A-1 (n=10), none of the 10 rats survived to 3 h; while in the hypothermia-O(2) group A-2 (n=5), all rats survived to 24 h (P<0.001). With HS of 180 min, in the normothermia-air group B-1 (n=10), three of 10 rats survived to 3 h and 24 h (hypotension during HS in these three survivors was less severe than in the non-survivors); and in the hypothermia-O(2) group B-2 (n=10) all 10 rats survived to 24 h (P<0.003). We conclude that moderate hypothermia (32 degrees C) plus 100% oxygen inhalation during volume-controlled HS in awake rats mitigates hypotension and increases the chance of survival. It enables survival even after 3 h of moderate HS.

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Stern SA. Low-volume fluid resuscitation for presumed hemorrhagic shock: helpful or harmful? Curr Opin Crit Care 2001;7:422-30. [PMID: 11805545 DOI: 10.1097/00075198-200112000-00009] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]

D'Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. BRAIN RESEARCH. BRAIN RESEARCH REVIEWS 2001;36:60-90. [PMID: 11516773 DOI: 10.1016/s0165-0173(01)00067-4] [Citation(s) in RCA: 1443] [Impact Index Per Article: 60.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]

Behringer W, Kentner R, Wu X, Tisherman SA, Radovsky A, Stezoski WS, Henchir J, Prueckner S, Jackson EK, Safar P. Fructose-1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 min in dogs. An exploratory study. Resuscitation 2001;50:205-16. [PMID: 11719149 DOI: 10.1016/s0300-9572(01)00337-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]

Abstract

In our exsanguination cardiac arrest (CA) outcome model in dogs we are systematically exploring suspended animation (SA), i.e. preservation of brain and heart immediately after the onset of CA to enable transport and resuscitative surgery during CA, followed by delayed resuscitation. We have shown in dogs that inducing moderate cerebral hypothermia with an aortic arch flush of 500 ml normal saline solution at 4 degrees C, at start of CA 20 min no-flow, leads to normal functional outcome. We hypothesized that, using the same model, but with the saline flush at 24 degrees C inducing minimal cerebral hypothermia (which would be more readily available in the field), adding either fructose-1,6-bisphosphate (FBP, a more efficient energy substrate) or MK-801 (an N-methyl-D-aspartate (NMDA) receptor blocker) would also achieve normal functional outcome. Dogs (range 19-30 kg) were exsanguinated over 5 min to CA of 20 min no-flow, and resuscitated by closed-chest cardiopulmonary bypass (CPB). They received assisted circulation to 2 h, mild systemic hypothermia (34 degrees C) post-CA to 12 h, controlled ventilation to 20 h, and intensive care to 72 h. At CA 2 min, the dogs received an aortic arch flush of 500 ml saline at 24 degrees C by a balloon-tipped catheter, inserted through the femoral artery (control group, n=6). In the FBP group (n=5), FBP (total 1440 or 4090 mg/kg) was given by flush and with reperfusion. In the MK-801 group (n=5), MK-801 (2, 4, or 8 mg/kg) was given by flush and with reperfusion. Outcome was assessed in terms of overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, brain death or death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), and brain histologic damage scores (HDS, total HDS 0, no damage; >100, extensive damage; 1064, maximal damage). In the control group, one dog achieved OPC 2, one OPC 3, and four OPC 4; in the FBP group, two dogs achieved OPC 3, and three OPC 4; in the MK-801 group, two dogs achieved OPC 3, and three OPC 4 (P=1.0). Median NDS were 62% (range 8-67) in the control group; 55% (range 34-66) in the FBP group; and 50% (range 26-59) in the MK-801 group (P=0.2). Median total HDS were 130 (range 56-140) in the control group; 96 (range 64-104) in the FBP group; and 80 (range 34-122) in the MK-801 group (P=0.2). There was no difference in regional HDS between groups. We conclude that neither FBP nor MK-801 by aortic arch flush at the start of CA, plus an additional i.v. infusion of the same drug during reperfusion, can provide cerebral preservation during CA 20 min no-flow. Other drugs and drug-combinations should be tested with this model in search for a breakthrough effect.

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Takasu A, Prueckner S, Tisherman SA, Stezoski SW, Stezoski J, Safar P. Effects of increased oxygen breathing in a volume controlled hemorrhagic shock outcome model in rats. Resuscitation 2000;45:209-20. [PMID: 10959021 DOI: 10.1016/s0300-9572(00)00183-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]

Abstract

It is believed that victims of traumatic hemorrhagic shock (HS) benefit from breathing 100% O(2). Supplying bottled O(2) for military and civilian first aid is difficult and expensive. We tested the hypothesis that increased FiO(2) both during severe volume-controlled HS and after resuscitation in rats would: (1) increase blood pressure; (2) mitigate visceral dysoxia and thereby prevent post-shock multiple organ failure; and (3) increase survival time and rate. Thirty rats, under light anesthesia with halothane (0. 5% throughout), with spontaneous breathing of air, underwent blood withdrawal of 3 ml/100 g over 15 min. After HS phase I of 60 min, resuscitation phase II of 180 min with normotensive intravenous fluid resuscitation (shed blood plus lactated Ringer's solution), was followed by an observation phase III to 72 h and necropsy. Rats were randomly divided into three groups of ten rats each: group 1 with FiO(2) 0.21 (air) throughout; group 2 with FiO(2) 0.5; and group 3 with FiO(2) 1.0, from HS 15 min to the end of phase II. Visceral dysoxia was monitored during phases I and II in terms of liver and gut surface PCO(2) increase. The main outcome variables were survival time and rate. PaO(2) values at the end of HS averaged 88 mmHg with FiO(2) 0.21; 217 with FiO(2) 0.5; and 348 with FiO(2) 1. 0 (P<0.001). During HS phase I, FiO(2) 0.5 increased mean arterial pressure (MAP) (NS) and kept arterial lactate lower (P<0.05), compared with FiO(2) 0.21 or 1.0. During phase II, FiO(2) 0.5 and 1. 0 increased MAP compared with FiO(2) 0.21 (P<0.01). Heart rate was transiently slower during phases I and II in oxygen groups 2 and 3, compared with air group 1 (P<0.05). During HS, FiO(2) 0.5 and 1.0 mitigated visceral dysoxia (tissue PCO(2) rise) transiently, compared with FiO(2) 0.21 (P<0.05). Survival time (by life table analysis) was longer after FiO(2) 0.5 than after FiO(2) 0.21 (P<0. 05) or 1.0 (NS), without a significant difference between FiO(2) 0. 21 and 1.0. Survival rate to 72 h was achieved by two of ten rats in FiO(2) 0.21 group 1, by four of ten rats in FiO(2) 0.5 group 2 (NS); and by four of ten rats of FiO(2) 1.0 group 3 (NS). In late deaths macroscopic necroses of the small intestine were less frequent in FiO(2) 0.5 group 2. We conclude that in rats, in the absence of hypoxemia, increasing FiO(2) from 0.21 to 0.5 or 1.0 does not increase the chance to achieve long-term survival. Breathing FiO(2) 0.5, however, might increase survival time in untreated HS, as it can mitigate hypotension, lactacidemia and visceral dysoxia.

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Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 2000;6:159-63. [PMID: 10655103 DOI: 10.1038/72256] [Citation(s) in RCA: 1199] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]