Hypothermia experimental studies

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

In addition, any proposed treatment with other agent(s) in conjunction with hypothermia will require very careful scrutiny of efficacy in preclinical models because of the marked benefit of hypothermia alone reported in many experimental studies. The addition of the alternative agent(s) must result in a clear-cut additional benefit compared with hypothermia treatment alone. Moreover, as previously discussed, it would be helpful to prove in both clinical and preclinical studies that each agent individually has some degree of benefit, as neither hypothermia nor neuroprotective pharmaceuticals have yet been definitively proven to be beneficial in clinical studies of acute stroke treatment. 

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. 

Kolhnar R, Henninger N, Bardutzky J, Schellinger PD, Schabitz WR, Schwab S. Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembohc stroke—an MRI study. Exp Neurol 2004 190 204-212. 

Decompressive hemicraniectomy was indirectly compared with moderate hypothermia (33°C) in a series of 36 patients from Georgiadis et al. They found a lower mortality rate for the patients who underwent hemicraniectomy (47% vs. 12%), as well as a lower complication rate. However, this was not a randomized study, and there was no comparison arm of patients who did not undergo either experimental therapy. 

Seki T. [Experimental and clinical study of safe prolongation of tourniquet time by hypothermia of an upper limb (author s transl)]. Nippon Seikeigeka Gakkai Zasshi 1980 54 721-37. 

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. 

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). 

Posttraumatic hyperthermia (>39°C), in contrast to hypothermia, has been shown in experimental models of TBI to worsen outcome. In one study, artificially elevating brain temperature to 39°C for a 3-h period, 24 h after moderate parasagittal F-P injury increased mortality, compared with normothermic rats (1). Delayed hyperthermia also significantly increased contusion volume and increased the frequency of abnormal-appearing myelinated axons. 

The mechanism of delayed neuronal injury following TBI includes apoptosis (63,64). Experimental data after cerebral hypoxic-ischemic injury indicate that moderate postinsult hypothermia (34°C) reduced the fraction of apoptotic cells but not cells undergoing necrosis (65). In another study, intraischemic hypothermia reduced the number of transferase dUTP nick-end labeling (TUNEL)-positive cells after transient focal ischemia (66). Thus, it will be important in future studies to determine whether hypothermia inhibits apoptotic neuronal cell death in models of TBI. 

Based on experimental and clinical data, cerebral hypothermia appears to be a potent therapeutic approach to treating brain trauma. However, recent results from the Multicenter National Brain Injury Study Hypothermia (NABIS H) clinical trial appear to be disappointing, and more refinement of the clinical application of hypothermia is required (73). Additional clinical trials are now required to evaluate systematically the beneficial effects of clinical hypothermia in different populations of brain-injured patients. In addition, experimental data regarding the beneficial effects of combination therapy are required to evaluate whether hypothermia plus pharmacotherapy may provide a better outcome. Forexample, mildpostischemichypothermia(33-39°C) combined with the antiinflammatory cytokine IL-10 has recently been reported to produce long-term protection of the C Al hippocampus after transient global ischemia (74). Hypothermia or IL-10 treatment alone did not protect chronically. In contrast, Kline etal. (75) showed that acute systemic administration of IL-10 suppressed the beneficial effects of... 

What is the evidence that hypothermia plus other potential neuroprotective therapies actually does improve outcome compared with individual neuroprotective agents Surprisingly, there are few preclinical and no human studies that have examined this issue. The main reason for this lack of study likely stems from the added complexity necessary for a combined treatment study, and the desire by most researchers to identify individual agents with neuroprotective properties first before proceeding to evaluate combination treatments. However, a handful of experimental treatment studies have been performed using hypothermia in conjunction with other neuroprotective agents, with surprisingly mixed results. 

These are the first clinical trials to demonstrate improved outcomes using hypothermia in this population of cardiac arrest patients. However, it s possible that some of the beneficial outcome in these studies was related to the prevention of hyperthermia. Experimental data have shown that even mild hyperthermia contributes to ischemic injury. 

Deliberate mild hypothermia has been shown to be an extremely effective means of neuroprotection during periods of ischemia in experimental models. Intraoperative mild hypothermia has become a standard of practice for many neurosurgeons performing complex intracranial procedures. Recent findings of neurologic benefit in prospective, randomized, controlled clinical studies of cardiac arrest patients are encouraging, but more research is required to confirm and extend these positive results to other patients with stroke and traumatic insults. Further investigation must be completed to establish the optimal time and duration when treatment should be instituted to offer the optimal protection for patients with acute ischemic and traumatic injuries. 

Extravasation of polymorphonuclear leukocytes (PMNs) in the area of injury occurs very early after injury in several different models of experimental TBI, and has been shown to correlate with the development of cerebral edema (101,102). Early canine studies conducted by Rosomoff (16,57) demonstrated that treatment with hypothermia decreased the posttraumatic cellular inflammatory response incited by experimental head injury compared to normothermic controls. This effect of hypothermia is likely mediated by several mechanisms including preservation of the BBB, thereby limiting extravasation of inflammatory cells and mediators into the area of injury (103), suppressing release of cytokines (22), and reducing CBF. 

It is known from animal models with global ischemia and traumatic brain injury that moderate hypothermia attenuates secondary brain damage by reducing cerebral ischemia and postischemic brain edema and preserving the blood-brainbarrier. Even though hypothermia has potent cerebroprotective effects after experimental focal ischemia, clinical studies on hypothermic therapy after MCA infarction were not available until recently. We performed a pilot study investigating the efficacy, feasibility, and safety of induced moderate hypothermia in the therapy of patients with acute, severe MCA infarction and increased ICP. 

Considering the results of recent studies in experimental animals, some groups studied the effect of moderate hypothermia (32-33 °C) on ICP in patients with ALF. Jalan et al. (2004) were able to show that cooling to 32 °C decreased ICP to <20 mm Hg even in patients with refractory intracranial hypertension. Although their results were quite impressive other groups call for a randomized, controlled... 

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