Mild hypothermia studies

Shiozaki T., Hayakata T., Taneda M., et al. (2001) A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia Study Group in Japan. J. Neurosurg. 94,50-54. 

In 1987, however, a study by Busto et al. (5) showed that small decreases in brain temperature (as little as 2-5°C below normal brain temperature) conferred a marked protective effect against experimental global cerebral ischemia. This finding, as well as subsequent animal studies that modeled neurodegenerative diseases and CNS injury, led to a resurgence of interest in mild hypothermia as a method of cerebral protection. 

Despite the variability in animal models, the ultimate goals of experimental studies on mild hypothermia are essentially the same ... 

The study of mild hypothermia in animal models requires an understanding not only of the clinical features that are to be replicated, but also of species-specific metabolic and behavioral patterns of the animals being used as well as proper endpoints. The successful transition from the laboratory to the clinical arena depends on a continuous exchange of information between clinical investigators and basic scientists. 

Discrepancies between results from the preliminary studies and the larger, multicenter trials remain to be elucidated. Significant intercenter variance in patient management (fluids, mean arterial blood pressure, ICP, and CPP) and treatment may have adversely affected the results of one of these trials (The National Acute Brain Injury Study Hypothermia) (61). Despite the overall negative findings, however, it is quite possible that certain subgroups of patients may benefit from treatment with mild hypothermia. 

Recently, two landmark prospective randomized controlled studies were published demonstrating the benefit of mild hypothermia in improving neurologic outcome in patients suffering cardiac arrest from ventricular fibrillation (73,74). 

The concept of neuroprotection relies on the fact that delayed neuronal injury occurs after ischemia, and each step along the ischemic cascade provides a target for therapeutic intervention. Thus, understanding the cellular and molecular mechanisms that underlie the development of neuronal and vascular injury is critical to optimize treatment. This chapter reviews experimental evidence from studies on focal cerebral ischemia and mild hypothermia, as well as the mechanisms involved in mild hypothermic neuroprotection. 

Mild hypothermia has been shown to reduce neurological deficits if started before, during, or after cerebral ischemia, but few studies have examined functional outcome in detail after experimental cerebral ischemia with hypothermia (29-33). 

We recently carried out a study (40) to determine the effects of delaying induction of mild hypothermia after transient focal cerebral ischemia and to ascertain whether the neuroprotective effects of mild hypothermia induced during the ischemic period are sustained over... 

When mild hypothermia was first shown to be beneficial, the assumption was that a substantial portion of its neuroprotective effect stemmed from a reduction in cerebral metabolism. However, studies on cerebral metabolic rate (CMR) made it clear that the degree of neuro-pathological injury following ischemia with mild hypothermic treatment did not correlate with the magnitude of metabolic depression observed (42). A reduction in temperature from 37°C to 34°C produces a 15-20% reduction in cerebral metabolism (approx 5-7% per °C), which is far less than the 50% decrease seen with electroencephalogram (EEG) silence. Furthermore, reductions in metabolism produced by anesthetics vs hypothermia are not equally neuroprotective (43). Thus, hypothermic neuroprotection cannot be explained by alterations in metabolic rate alone. 

Neurotransmitters such as glutamate interact with a variety of receptors that are coupled to second messenger systems. The effects of mild hypothermia on ischemia-induced changes in intracellular messenger systems and mediators have also been studied and are described in Chapter 2. 

The aforementioned findings in rodents mirror results observed in dogs subjected to cardiac arrest with subsequent postischemic mild hypothermia of 1- to 12-h duration (38-44). For example, a 12-h period of 34°C hypothermia with hemodilution and elevated blood pressure reduced brain injury (e.g., hippocampus, neocortex, basal ganglia) and lessened functional deficits after cardiac arrest. However, in all of these studies the survival time was 4 d or less, and thus it has yet to be proven that postischemic hypothermia can permanently reduce ischemic brain injury in the dog. Based on the rodent literature, it would be useful to investigate more protracted bouts of mild hypothermia and assess longterm outcome in this intensive cardiac arrest model in the dog. 

Studies in neonatal rats support these findings. For instance, Sirimanne et al. (58) persistently (21-d survival) reduced infarction in 21-d-old rats with 72 h of immediate postischemic mild hypothermia. Gunn et al. (59) reduced cortical infarction (5-d survival) in fetal sheep with the use of 72 h of mild in utero hypothermia induced 90 min after... 

The effect of hypothermia in combination with thrombolytics has also been evaluated in only a few experimental studies. Meden et al. (11) studied differences in thrombolytic effectiveness in a rat embolic stroke model. In this study, 2 h of intraischemic hypothermia was administered with or without thrombolytic therapy. Thrombolysis was initiated at 2 h after ischemia onset. The investigators found that both hypothermia and thrombolysis significantly reduced infarct volume, but they could not demonstrate any added benefit of thrombolysis over hypothermia alone. A recent study by Wang et al. (12) used a focal embolic brain ischemia model to study the effects of minocycline, an antiinflammatory agent, alone or in combination with mild hypothermia (34—35°C started 1 h after embolization, 2-h duration). The results showed that both minocycline and the hypothermia-minocycline combination reduced infarct volume significantly, but no additive effect was observed. 

Mild hypothermia has gained attention in recent years after laboratory studies showed a significant reduction in ischemic neuronal death... 

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