Hypothermia with treatment

Coimbra C., Drake M., Boris-Moller F., and Wieloch T. (1996) Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia. Stroke 27,1578-1585. 

The specific choice of treatments to be used in combination with hypothermia could be based on a variety of different approaches. First, there could be a direct synergistic effect between hypothermia and the other proposed treatment modality, presumably as a result of a complementary mode of action. For example, combining hypothermia with thrombolytic therapy might be an appropriate pairing in which the hypothermia prolongs the therapeutic window for subsequent definitive reperfusion. Similarly, hypothermia could be used just after thrombolysis, to prevent reperfusion induced injury and prolonging the viability of injured but not irreversibly damaged tissue. 

What are the potential pitfalls of combining hypothermia with other treatment modalities Perhaps the most important is the possibility that there will be some adverse interaction between the combined treatments. This is not a minor concern, as it is well known that many pharmaceutical agents exhibit adverse effects when used in combination with other agents. Many of these adverse effects can be serious if not life threatening. In fact, this problem with drug interactions is a major reason why many pharmaceutical treatments are not used in clinical practice. 

Nevertheless, the possibility of combining hypothermia with other types of neuroprotection or thrombolysis is intriguing, and certainly deserves future study. However, if this treatment is ever to impact clinical practice, it is essential that appropriate preclinical studies be conducted. In particular, the rigorous evaluation of these combinations in a variety of ischemic models that most closely simulate the pathophysiology of acute ischemic stroke, is needed. Only after such extensive testing should the possibility of combination therapy be subsequently evaluated in randomized clinical trials. 

Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998 29 2461-2466. 

There is a good deal of evidence that the therapeutic effects of antidepressants could involve adaptive changes in 5-HTia receptors. Postsynaptic 5-HTia receptor responses became implicated because the hyperpolarisation of hippocampal CA3 pyramidal neurons that follows ionophoretic administration of 5-HT was found to be increased after chronic treatment with most (but not all) antidepressants (Chaput, de Montigny and Blier 1991). Others suggested that antidepressants attenuate postsynaptic 5-HTja responses because the hypothermia, evoked by their activation, is diminished by antidepressants (Martin et al. 1992). 

In the first 2 weeks post-MI, caution is advised and careful dose titration is especially important, particularly in patients with markedly impaired ventricular function. Intraoperative and postoperative tachycardia and hypertension Do not use esmolol as the treatment for hypertension in patients in whom the increased blood pressure is primarily caused by the vasoconstriction associated with hypothermia. Renal/Hepatic function impairment Use with caution. 

In CONCLUSION, the future drug treatment of stroke will probably depend on a combination of both neuroprotection (e.g. hypothermia, glutamate receptor antagonists, free radical scavengers, etc.) with thrombolysis which attempts to re-establish normal blood flow. Such treatments may help to expand the window between the initial ischaemic episode and brain damage. Whether any of the drugs mentioned here will ultimately be of any value in the prevention and / or treatment of stroke is still a matter of conjecture. 

Direct cardiac delivery into adults can be performed via the vector transfer procedure described by Ikeda et al. (2002). Briefly, animals are anesthetized with an intraperitoneal injection of sodium pentobarbital (75 mg/kg), and ventilated. The right carotid artery is then cannulated with a catheter placed at the aortic root. The animal is then placed under induced hypothermia until the body core temperature drops to below 26 °C. The ascending aorta and pulmonary arteries are occluded and histamine pre-treatment is delivered to the aorta (20 mmol/1, volume 2.5 ul/g, body weight) for 3 min. The vector solution is then injected, the occlusions released 30 s later and the animal is resuscitated. 

The thrombolysis algorithm is based on the assumption that the hypotheses discussed above are proven to be correct. That is, primarily (1) the presence of significant perfusion-diffusion mismatch (qualitatively +/- quantitatively assessed) predicts treatment response, and (2) a large DWI lesion (qualitatively > V2 MCA territory, and/or quantitatively > 100 cm3) predicts haemorrhagic transformation. Patients excluded from thrombolysis because of extensive DWI lesions with or without perfusion-diffusion mismatch maybe considered for more aggressive measures such as hypothermia or decompressive hemicraniectomy (Schwab et al. 1998,2001). 

Another large prospective, randomized multicenter trial was recently published and echoed results from the studies just mentioned (7). In this trial, a total of 392 patients with severe TBI (GCS scores of 3-8) were randomly assigned for treatment with hypothermia (core temperature of 33°C, 48-h duration), which was initiated within 6 h after injury by means of surface cooling, or with normothermia. The results showed poor outcome in both temperature groups and no difference in mortality rate. There was, however, a beneficial effect in patients younger than 45 yr of age in whom hypothermia was present on admission. While hypothermia was able to reduce the ICP in patients with intracranial... 

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. 

Azzopardi D., Robertson N. J., Cowan F. M., Rutherford M. A., Rampling M., and Edwards A. D. (2000) Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics 106, 684—694. 

Dietrich W. D., Lin B., Globus M. Y., Green E. J., Ginsberg M. D., and Busto R. (1995) Effect of delayed MK-801 (dizocilpine) treatment with or without immediate postischemic hypothermia on chronic neuronal survival after global forebrain ischemia in rats. J. Cerebr. Blood Flow Metab. 15, 960-968. 

Colbourne F., Sutherland G., and Corbett D. (1997) Postischemic hypothermia. A critical appraisal with implications for clinical treatment. Mol. Neurobiol. 14, 171-201. 

The mechanisms whereby brain cells die during ischemia are not fully understood. Experimental evidence points to a complex array of parallel hemodynamic, biochemical, and electrophysiological events that combine to produce neuronal damage. In experimental cerebral ischemia, the severity of this damage can be significantly reduced by treatment with mild hypothermia (2-5°C below normal brain temperature). 

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