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J Thorac Cardiovasc Surg 2007;134:1382-1383
© 2007 The American Association for Thoracic Surgery
Letter to the Editor |
a Department of Anatomy, Histology and Embryology, University of Ioannina, School of Medicine, Ioannina, Greece
b Department of Cardiovascular Surgery, University of Ioannina, School of Medicine, Ioannina, Greece
Although the deleterious effects of prolonged exposure to cardiopulmonary bypass on brain function and structure have been demonstrated, neuroprotective strategies, particularly deep hypothermia and circulatory arrest (DHCA), remain an issue of debate. This is related in part to the gap between the experimental understanding of brain injury and the clinical application of various neuroprotective strategies. As suggested by Dr Augoustides, this gap can be attributed to the lack of clinically relevant guidelines for effective laboratory study of circulatory arrest.
Our goal was to assess one possible mechanism of neuronal injury after DHCA. Because apoptosis seems to involve a subtle and complex cascade of events, the paradigm applied, although not totally clinically relevant, would allow a robust response for assessment. Further study is clearly warranted to unravel relevant mechanisms and sensitive markers, which in turn would allow us to appreciate the potential clinical relevance of these experimental findings. Dr Augoustides makes a valid point for the need to develop appropriate guidelines that would enhance this investigative process.
Evaluating various strategies in animal studies to determine clinical feasibility has been limited to large-animal models (porcine, canine, and ovine). These are expensive, demanding, and usually performed without neuropsychologic assessment. Each model system, however, from cell cultures to rats, large animals, and ultimately clinical trials, has its advantages and disadvantages, and its place in these investigations.
Most animal models require an extended period of arrest to produce a reproducible level of neuronal injury that would facilitate elucidating the mechanisms of injury and efficacy of neuroprotective interventions. Many large animal models require DHCA for at least 90 to 120 minutes to demonstrate neurologic deficits.1,2
Although such prolonged DHCA intervals might not be considered clinically realistic, they may be more appropriate for demonstrating the molecular pathways behind acute neuronal injury and thus modes of intervention.
Study of a neuroprotective strategy includes the appropriate selection of an animal model and functional indices. The model is selected with respect to the relevance and feasibility of assessing the parameters of interest. Investigations of promising neuroprotective methods require validation (validation study), use in experimental settings to optimize cerebral protection during cardiopulmonary bypass and DHCA (performance study), and test during routine cardiac surgery (clinical study).
A clearer understanding of the consequences of DHCA will be pivotal in clinical decision-making, including when to initiate circulatory arrest and the appropriate interval. Delayed cell death is of special interest because of the potential for intervention. Although apoptosis is believed to play a part in cerebral injury, its role has generally been identified through histologic techniques. These snapshots do not permit a clear delineation of the timeline of apoptosis. Because the role of apoptosis is not clear, therapies have yet to be designed for the specific purpose of inhibiting apoptosis.
There are still many gaps in our knowledge about how to best study cerebral outcome. Investigations require coordinated efforts by multiple groups, pursuing systematic, multilevel research, spanning from cell cultures, to various animal models, and ultimately to clinical trials.
References
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