Original ArticleEarly Transient Mild Hypothermia Attenuates Neurologic Deficits and Brain Damage After Experimental Subarachnoid Hemorrhage in Rats
Introduction
After the onset of ischemia, energy failure results in the breakdown of membrane potentials and a loss of cellular electrolyte gradients and cellular compartmentation. Metabolic pathways stop working appropriately and the cell enters a detrimental cascade of ischemic damage. Therapeutic interventions that aim at preserving energy metabolism or at preventing the depletion of energy substrates may therefore offer tissue protection. The neuroprotective effect of hypothermia in ischemic conditions of the brain is undisputed. Deep hypothermia is therefore routinely used in cardiac surgery. During the last 3 decades, the neuroprotective properties of moderate or even mild hypothermia have been evaluated in various experimental models of traumatic and ischemic brain damage1, 2, 3, 4 and are summarized in Table 1. Mild hypothermia has shown an extraordinarily high tissue protective effect in literally all experimental studies.15, 20, 32, 35 However, the effect of mild hypothermia has not been reproducible in clinical studies of traumatic brain injury36 and is being tested in embolic stroke.37 The reason for its lack of efficiency in clinical trials may be that the stage of irreversible damage may largely have already been entered by the time the patients are admitted to hospital, a diagnosis is found, and treatment can be started. Experimental studies on the neuroprotective effect of mild hypothermia after subarachnoid hemorrhage (SAH) are rare (because SAH differs from ischemic stroke and traumatic brain injury in its pathophysiology) and therapeutic mild hypothermia may simply have been initiated too late.
Different from ischemic stroke and traumatic brain injury, where ischemia and primary brain injury usually occur simultaneously, ischemic lesions in patients with aneurysmal SAH and post-SAH vasospasm usually occur as delayed cerebral ischemia, because the initial global ischemia is followed by a long-lasting and persistent low-flow status, which bears the danger of progressive energy exhaustion. Therefore, timing is definitely the issue in our perspective.
Applied early enough, mild hypothermia may prevent energy depletion and have a neuroprotective effect. In a small clinical series, Karamatsu et al.38 found that patients with SAH may profit from treatment with very mild hypothermia if started early after SAH.
The new idea in our hypothesis is that mild hypothermia, applied early enough within the right time frame in the early hours after SAH in which the low-flow status is still happening and delayed ischemia is still ahead of the patient, could therefore have a neuroprotective effect. The present study was conducted in the framework of a larger-scale project assessing the neuroprotective properties of various treatment forms in the early stage of SAH. It investigated the effects of mild hypothermia induced in the first minutes after experimental SAH in rats on hemodynamic parameters, functional outcome, and tissue damage.
Section snippets
Methods
For the experiments, 20 male Sprague-Dawley rats (300–350 g body weight), purchased from Charles-River, Sulzfeld, Germany were used. All experiments were approved by the regional authorities and the district government of Bavaria, Germany.
Physiologic Parameters
Values of pH, PaCo2 (arterial tension of carbon dioxide), and Pao2 (arterial tension of oxygen) are presented in Table 2. Differences between the groups were not significant.
MABP, ICP, Cerebral Perfusion Pressure
MABP increased in the control group after the induction of SAH from a baseline of 83 ± 19 mm Hg to a maximum of 89 ± 15 mm Hg after 5 minutes and then declined to 78 ± 17 mm Hg and 78 ± 22 after 1 and 3 hours. In the hypothermia group, MABP increased from a baseline of 85 ± 23 mm Hg to a maximum of 87 ± 22 mm Hg 30 minutes
Discussion
Like many other experimental studies of various kinds of brain damage, the results of this study show a strong neuroprotective effect of moderate hypothermia in an animal model of SAH. The experiments were conducted in the framework of a project investigating various forms of emergency treatment in the acute phase of SAH that can potentially be transferred into clinical emergency medicine. For this purpose, well-established drugs and treatment measures are evaluated for their ability to
Conclusions
This study shows that the induction of mild hypothermia immediately after experimental SAH can reduce ICP and improve CBF in the early course of the disease. Although hypothermia may not inhibit lesion growth, it has shown its neuroprotective effect in this study. Because there is no relevant contraindication for mild hypothermia in any thinkable differential diagnosis to SAH, it may readily be applied in patients as a first-tier therapy and could even be used by emergency rescue services
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Conflict of interest statement: T.W. received lecture fees from Medtronic. All other authors have no conflict to declare.