Elsevier

Resuscitation

Volume 75, Issue 1, October 2007, Pages 105-113
Resuscitation

Experimental paper
Long-lasting cognitive injury in rats with apparent full gross neurological recovery after short-term cardiac arrest

https://doi.org/10.1016/j.resuscitation.2007.02.017Get rights and content

Summary

Objective

The long-term behavioral effects of mild global ischemia have not been well described. We used short (5 min) asphyxic-cardiac arrest that resulted in no apparent gross neurological deficits to study the long-term effects of mild hypoxic ischemia on the neurobehavioral status of rats.

Methods

Fifteen adult, male Wistar rats were studied. One group was given asphyxic-cardiac arrest (CA) for 5 min (n = 10) and the other group had Sham procedure (n = 5). Neurobehavioral testing was performed before and 2 weeks after CA. The neurobehavioral evaluations were: neurological deficit score (NDS), Y Maze, open field, pre-pulse inhibition (PPI) of acoustic startle reflex (ASR), wire hanging, and inclined screen.

Results

At 24 h post-CA, all of the rats regained normal neurological function as measured by NDS, an integral score for consciousness, brainstem reflexes, sensorimotor function and simple behavioral reflex tests. However, 1 week after CA, the rats exhibited significant activity reductions in the open field and in spontaneous alternation in the Y maze. The CA rats also showed a significant decrease in startle reaction amplitude and startle inhibition in the PPI tests. Two weeks after CA, the changes in motor activity and deficits in PPI remained significant, but the spontaneous alternation recovered. The muscle strength test of wire hanging and inclined screen tests did not exhibit significant change.

Conclusion

We present a rodent model of mild CA that, despite apparent full recovery of global neurological function at 24 h post-resuscitation, exhibited long-term cognitive injury lasting for at least 2 weeks after CA. This model may help understand better the injury associated with CA and develop management strategies for mild brain injury.

Introduction

A significant focus of research in relation to functional outcome after resuscitation from cardiac arrest has been mainly on those with moderate to severe neurological injury. Such studies have shown that survivors of out-of-hospital cardiac arrest, typically with longer periods of ischemia, tend to develop cognitive dysfunction, including, but not limited to, memory impairment.1, 2, 3, 4, 5 Outcomes of short-term cardiac arrest are less studied. Patients with short duration cardiac arrest and rapid emergence from coma have demonstrated long-term neurological impairments that limit their return to previous levels of function.6, 7 Memory deficits have been documented repeatedly in humans who survived varying times of cardiac arrest.8, 9

Studies in rodent models show that full, functional neurological recovery within 24 h of a mild cardiac arrest (3–5 min of asphyxial cardiac arrest), as measured by a neurological deficit score (NDS) can be attained.10 However, many aspects of the intermediate functional recovery to long-term cognitive outcome have not been fully evaluated. Some evidence of subtle behavioral impairments exists for cardiac arrest of 6 min or more duration. Hendrickx et al. studied mild-moderate asphyxia (6 min) in rats and found that both spontaneous locomotor activity and passive avoidance were affected in CA rats, compared to Sham rats.11 Dhooper et al. found that rats which underwent a moderate injury with 7 min asphyxia showed an increase in anxiety in the elevated plus maze, which lasted for at least 115 days post-ischemia, and a temporary decrease in motor activity, which recovered by day 15.12 A forelimb use bias as tested by the cylinder test13 was noticeably different between Sham and ischemia groups at 1 week post-ischemia, but not so at 2 weeks post-ischemia14, 15. Li et al. also performed many tests, including the wire hanging test, but found that only the corner test, which tested integrated sensorimotor function, was able to distinguish differences between the groups long-term.15. Kofler et al. found that cardiac arrest decreased spontaneous alternation in T maze tests in mice up to 7 days post-CA, but did not decrease locomotor activity in open field tests.16 Hickey et al. have demonstrated that a moderate injury of 7 min asphyxia can increase amplitudes and shorten latencies of acoustic startle reflex.17 There have been other studies that have demonstrated cognitive deficits in spatial learning and working memory tasks.18, 19, 20, 21

As resuscitation techniques improve and novel therapies for brain injury post-CA are developed, more patients are expected to have improvement in survival and gross neurologic function but may be at risk of long-term neuro-cognitive impairment. Animal models of milder injuries or rapid recoveries after CA, which could serve as experimental platforms, have not been established. We undertook a study to test the hypothesis that shorter asphyxial CA (5 min) in rats with rapid recovery to grossly normal function will have long-term functional deficits on neurobehavioral testing.

Section snippets

Animals

The Animal Care and Use Committee of the Johns Hopkins Medical Institutions approved the experimental protocol used in this study. Fifteen adult, male Wistar rats (300–350 g) were studied. The 10 rats that were selected for CA underwent this procedure; the five Sham rats did not undergo any surgical procedure or receive any CA. All rats were behaviorally tested before and during 2 weeks post-CA.

Cardiac arrest, resuscitation and post-operative care

Anesthesia was induced with 4% halothane and 50% oxygen (O2) +50% nitrogen (N2) at 4 l/min and followed

Neurodeficit score

At 6 h post-resuscitation, the 5-min rats were fairly well recovered by NDS (67.3 ± 5.3) as compared to the Sham rats that showed a normal level of neurologic function (80.0 ± 0.0). For reference, the NDS of 5-min CA rats studied were midway in severity between the 3-min rats, which were near-normal (75.0 ± 4.2), and the 7-min rats, which were severely impaired (37.8 ± 1.6). By 24 h, both the 3-min and 5-min rats had recovered normal function (80.0 ± 0.0 and 79.3 ± 1.7, respectively), while the 7-min rats

Discussion

Our findings demonstrate that rats are able to have apparently normal neurological function within 24 h after resuscitation from a 5 min period of asphyxia. Semi-quantitative observations of the rats using a scoring system for consciousness, brainstem reflexes, sensorimotor function and simple behavioral reflexes show normal neurological function and infer normal everyday behavioral functions However, when tested with a series of focused neurobehavioral tests 1 and 2 weeks post-CA, deficits in

Conclusion

The results of our experiments suggest that there is cognitive injury in rats that show apparently full functional neurological recovery within 24 h of a mild CA. While mild yet impairing injuries have been recognized in CA survivors, they have not been the focus of detailed research. We believe that this model will allow us to understand the injury and recovery processes better and provide a great opportunity to develop more specific methods of therapy for this patient population, including

Conflict of interest statement

There are no conflicts of interest for this study.

Acknowledgements

Study support: NIH-RO1-NS-24282.

References (41)

Cited by (16)

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    The cardiac arrest and resuscitation model of global cerebral ischemia produces transient complete ischemia of the whole body followed by resuscitation-based revival (Hendrickx et al., 1984; Katz et al., 1995). Mild cardiac arrest results in long-term behavioral deficits when assessed using behavioral tests like Y Maze test and open field test (Schreckinger et al., 2007). In the light of epidemiological data showing a high frequency of cardiac arrest among diabetics and non-diabetics, this model promises to study brain damage associated with cardiac arrest among diabetics (Hoxworth et al., 1999; Valles et al., 2006).

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A Spanish translated version of the summary of this article appears as Appendix in the final online version at 10.1016/j.resuscitation.2007.02.017.

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