Experimental paperLong-lasting cognitive injury in rats with apparent full gross neurological recovery after short-term cardiac arrest☆
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)
- et al.
The first year after successful cardiac resuscitation: function, activity, participation and quality of life
Resuscitation
(2005) - et al.
Cognitive impairment in survivors of out-of-hospital cardiac arrest
Am Heart J
(2004) - et al.
Assessment of quality of life and cognitive function after out-of-hospital cardiac arrest with successful resuscitation
Am J Cardiol
(2004) - et al.
Poor outcome after hypoxia-ischemia in newborns is associated with physiological abnormalities during early recovery. Possible relevance to secondary brain injury after head trauma in infants
Exp Toxicol Pathol
(1999) - et al.
A novel quantitative EEG injury measure of global cerebral ischemia
Clin Neurophysiol
(2000) - et al.
Asphyxia, cardiac arrest and resuscitation in rats. II. Long term behavioral changes
Resuscitation
(1984) - et al.
Ischemia-induced anxiety following cardiac arrest in the rat
Behav Brain Res
(1997) - et al.
Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender
Exp Neurol
(2004) - et al.
Histopathological and behavioral characterization of a novel model of cardiac arrest and cardiopulmonary resuscitation in mice
J Neurosci Meth
(2004) - et al.
Cognitive deficits induced by global cerebral ischaemia: prospects for transplant therapy
Pharmacol Biochem Behav
(1997)
Cognitive deficits induced by global cerebral ischaemia: relationship to brain damage and reversal by transplants
Behav Brain Res
Differential effects of global ischemia on delayed matching- and non-matching-to-position tasks in the water maze and Skinner box
Neurobiol Learn Mem
Reference and working memory of rats following hippocampal damage induced by transient forebrain ischemia
Physiol Behav
Neurological recovery by EEG bursting after resuscitation from cardiac arrest in rats
Resuscitation
The cognitive effects of ovariectomy and estrogen replacement are modulated by aging
Neuroscience
Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests
Brain Res
The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review
Eur J Pharmacol
Infralimbic D1 receptor agonist effects on spontaneous novelty exploration and anxiety-like defensive responding in CD-1 mice
Behav Brain Res
Cardiac arrest: long-term cognitive and imaging analysis
Resuscitation
Quantitative EEG and neurological recovery with therapeutic hypothermia after asphyxial cardiac arrest in rats
Brain Res
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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.