Hypothermia combination

Chapter 6 / Hypothermia Combined With Other Treatments... 

Kahveci et al. (13) compared the cerebral protective effects of two known protective anesthetics, isoflurane and propofol, in combination with hypothermia (33-34°C) after traumatic brain injury (TBI). In that study, the authors found that propofol anesthesia plus hypothermia following TBI was better than the isoflurane-hypothermia combination because it reduced intracranial pressure and increased cerebral perfusion pressure under those conditions. 

Preclinical Experimental Criteria for Hypothermia Combination Treatment in Acute Stroke... 

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. 

Els T, OehmE, Voigt S, Klisch J, Hetzel A, Kassubek J. Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis 2006 21(l-2) 79-85. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

Combine OTC sleep aids with alcohol or prescription sleep aids such as benzodiazepines or barbiturates. This can lead to severe sedation, morning sleepiness, hypothermia, and even reduced breathing. 

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. 

The need to cool patients quickly while at the same time reducing complication rates has led to the development of simpler methods of rapidly inducing and maintaining hypothermia. More modest hypothermia can now be achieved in awake patients with acute stroke by surface cooling with the forced air method in combination with pethidine to treat shivering (75), and several intravenous vascular cooling techniques look encouraging (48-50). 

MunakataM., Kato R., YokoyamaH., etal. (2000) Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy. Brain Dev. 22,373-377. 

OhtsukiN., KimuraS., Nezu A., and Aihara Y. (2000) [Effects of mild hypothermia and steroid pulse combination therapy on acute encephalopathy associated with influenza virus infection report of two cases]. No To Hattatsu 32, 318-322. 

Pazos A. J., Green E. J., Busto R., et al. (1999) Effects of combined postischemic hypothermia and delayed A-tert-butyl-alpha-pheylnitrone (PBN) administration on histopathological and behavioral deficits associated with transient global ischemia in rats. Brain Res. 846, 186-195. 

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). 

Frazzini et al., 1994 Wistar rats MCAo Permanent 33 and 37, intraischemia, with or without MK-801 before or after ischemia Infarct volume 24 h postischemia Both hypothermia and MK-801 reduced infarct size no further reduction when combined... 

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... 

Combination Therapy With Hypothermia and Pharmaceuticals for the Treatment of Acute Cerebral Ischemia... 

There are many potential advantages to the use of hypothermia in combination with other neuroprotective agents. It is assumed that by... 

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. 

Potential Barriers to Combination Hypothermia and Neuroprotective Treatment in Acute Ischemic Stroke... 

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. 

For hypothermia, one major possible difficulty involves the effect of low temperature on metabolism and enzyme activity. Many pharmaceutical agents have reduced biological activity at lower temperature compared with higher temperature. The thrombolytic activity of recombinant tissue plasminogen activator (rt-PA), for example, is clearly temperature dependent, with decreased activity at lower temperature (1). Thus, the assumption that hypothermia will not have an adverse effect on other treatment agents cannot be presumed. Hypothermia is also known to reduce the activity of inflammatory and antiinfectious biological processes. This could potentially result in increased susceptibility to infection. This possibility is of particular concern because infections are a major cause of morbidity in stroke patients (2). Therefore, combination therapy with hypothermia and antiinflammatory agents could potentially worsen outcome. 

Similarly, hypothermia has known effects on cardiac rhythm, electrolyte balance, and metabolism, all of which could be enhanced when combined with pharmaceutical agents such as calcium or other ion channel blockers. Thus, as with all possible treatments, there is the potential not only for improvement, but also significant harm if an inappropriate combination is employed. 

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. 

The neuroprotective effects of other compounds have also been demonstrated to be enhanced when combined with hypothermia. Guan et al. (6) evaluated the efficacy of hypothermia in combination with insulinlike growth factor (IGF) using a modified Levine hypoxic-ischemic model (right carotid ligation plus 10 min of hypoxia in neonatal animals). In this study, the use of hypothermia resulted in a significant extension of the therapeutic time window. Recovery in a cool vs a warm environment (23 C vs 31 C) extended the effectiveness of IGF-1 by up to 4 h. 

Similarly, Schmid-Elsaesser et al. (7) reported a synergistic effect of hypothermia when added to therapy with either tirilizad or magnesium (Mg). In this study, rats were subjected to transient ischemia of 90 min duration using a suture occlusion model. Hypothermia was administered intraischemically and animals were rewarmed simultaneous with reperfusion. Subjects were treated with various combinations of the three agents, in a systematic fashion. A stepwise increase in the reduction in infarct volume was observed between Tirilizad + Mg, hypothermia alone, and hypothermia + tirilizad + Mg in combination. 

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. 

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