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Aging and disease    2018, Vol. 9 Issue (1) : 31-39     DOI: 10.14336/AD.2017.0221
Orginal Article |
Novel Modification of Potassium Chloride Induced Cardiac Arrest Model for Aged Mice
Liu Huaqin1,2, Yu Zhui1,3, Li Ying1,4, Xu Bin1,5, Yan Baihui1,6, Paschen Wulf1, Warner David S1, Yang Wei1, Sheng Huaxin1,*
1The Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
2Department of Anesthesiology, The 4th Hospital of Hebei Medical University, Shijiazhuang, China
3Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
4Department of Cardiology, The 5th Hospital of Tianjin, Tianjin, China
5Department of Environmental Health, China Medical University, Shenyang, China
6Department of Anesthesiology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Abstract  

Experimental cardiac arrest (CA) in aging research is infrequently studied in part due to the limitation of animal models. We aimed to develop an easily performed mouse CA model to meet this need. A standard mouse KCl-induced CA model using chest compressions and intravenous epinephrine for resuscitation was modified by blood withdrawal prior to CA onset, so as to decrease the requisite KCl dose to induce CA by decreasing the circulating blood volume. The modification was then compared to the standard model in young adult mice subjected to 8 min CA. 22-month old mice were then subjected to 8 min CA, resuscitated, and compared to young adult mice. Post-CA functional recovery was evaluated by measuring spontaneous locomotor activity pre-injury, and on post-CA days 1, 2, and 3. Neurological score and brain histology were examined on day 3. Brain elF2α phosphorylation levels were measured at 1 h to verify tissue stress. Compared to the standard model, the modification decreased cardiopulmonary resuscitation duration and increased 3-day survival in young mice. For aged mice, survival was 100 % at 24 h and 54% at 72 h. Neurological deficit was present 3 days post-CA, although more severe versus young mice. Mild neuronal necrosis was present in the cortex and hippocampus. The modified model markedly induced elF2α phosphorylation in both age groups. This modified procedure makes the CA model feasible in aged mice and provides a practical platform for understanding injury mechanisms and developing therapeutics for elderly patients.

Keywords cardiac arrest      resuscitation      mouse model      aging     
Corresponding Authors: Sheng Huaxin   
About author:

These authors contributed equally to this work.

Issue Date: 01 February 2018
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Liu Huaqin
Yu Zhui
Li Ying
Xu Bin
Yan Baihui
Paschen Wulf
Warner David S
Yang Wei
Sheng Huaxin
Cite this article:   
Liu Huaqin,Yu Zhui,Li Ying, et al. Novel Modification of Potassium Chloride Induced Cardiac Arrest Model for Aged Mice[J]. Aging and disease, 2018, 9(1): 31-39.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0221     OR     http://www.aginganddisease.org/EN/Y2018/V9/I1/31
Figure 1.  Diagram of the modified mouse cardiac arrest model

The difference from other models is that blood was withdrawn from jugular vein before onset of cardiac arrest to enable use of a small amount of KCl (30 µl 0.5 M) to induce cardiac arrest. Blood was re-infused 3 minutes following cardiac arrest onset. LDF = laser Doppler flow, MAP = mean arterial blood pressure and EKG = electrocardiography.

Figure 2.  Electrocardiography (EKG) and mean arterial blood pressure (MAP) changes in cardiac arrest

(A) pre-injury phase, (B) cardiac arrest onset, (C) initial resuscitation phase (D) resuscitation phase with absent blood pressure, (E) late resuscitation phase, (F) recovery phase following resuscitation. For the x-axis in A-F, each square = 0.25 sec.

Rectal Temperature (°C)Mean Arterial Pressure (mmHg)LDF
(% baseline)
Pre
CA-4
CA-8
R-5
R-10
R-20
R-30
37.3 ± 0.2
36.7 ± 0.4
35.9 ± 0.5
34.8 ± 0.5
34.4 ± 0.5
33.3 ± 0.7
32.5 ± 0.6
78 ± 2
7 ± 1
6 ± 1
123 ± 22
58 ± 12
66 ± 16
82 ± 14
100
2 ± 1
2 ± 0
64 ± 8
54 ± 12
77 ± 21
87 ± 38
Table 1  Physiologic values during cardiac arrest and resuscitation.
Figure 3.  Resuscitation time and % survival over 72 h in young adult cardiac arrest mice subjected to 30 µl- or 50 µl KCl-induced cardiac arrest (n=5/group)

(A) resuscitation time; (B) Survival rate. Squares represent individual mice. Horizontal bars represent mean±SD, * P<0.05 vs. 50 µl KCl group.

Figure 4.  Resuscitation duration, functional recovery and survival curve in aged cardiac arrest mice (n=9-10/group)

(A) resuscitation time, (B) survival curve, (C) neurological score, (D) spontaneous motor activity. * P<0.05 vs. young adult group.

Figure 5.  Representative brain histology 3 days post-cardiac arrest

(A) hippocampal CA1, (B) cortex, (C) dentate gyrus, (D) thalamus. Arrows point to dead neurons.

Figure 6.  Spontaneous locomotor activity of aged mice subjected to cardiac arrest or sham surgery with rectal temperature controlled at 37ºC until 30 min after resuscitation onset

Injured mice had a significant decline of spontaneous activity time (A) and travel distance (C) compared to sham group (p<0.01). An effect of ischemia on velocity (B) was not detected.

Figure 7.  Endoplasmic reticulum stress in brain at 1 h post-CA

The level of phosphorylated elF-2α expressed as the ratio of β-actin. * P<0.05 vs. sham group.

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