Hypothermia with

Georgiadis et al. Stroke 2002 33(6) 1584-1588 Nonblinded prospective hemicraniectomy for nondominant and cooling for dominant hemisphere 19 of 36 tx with hypothermia Hypothermia to 33°C with cooling blankets or endovascular technique on clinical course in pts with >2/3 MCA infarct 12% vs. 47% mortality for surgery vs. hypothermia. Hypothermia with increased complications of hypotension and electrolyte abnormalities. Both tx with longer ICU course... 

Nishio et al., 2002 Cats MCAo 1 h, with reperfusion 30.5 and 36.5, intraischemia plus 3 h, with slow or rapid rewarming Somatosensory evoked potentials (SEPs), edema at 5 h reperfusion Edema reduced in hypothermia with slow re warming, recovery of SEPs enhanced with slow rewarming... 

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. 

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. 

Transfusion of refrigerated blood, especially during massive transfusions or during exchange transfusions, can induce hypothermia, with a danger of cardiac arrest. If several units of blood are to be rapidly administered, they should be warmed, but not overheated, before transfusion (32). 

Dixon SR, Whitboum RJ, Dae MW, et al. Induction of mild systenuc hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002 40 1928-1934. 

Hypothermia with a core temperature of less than 32°C (90°F) often causes an extra terminal QRS deflection (J wave or Osborne wave), resulting in a widened QRS appearance (Figure 1-6). 

Drug interactions anticonvulsants (phenytoin, barbiturates, carbamazepine) increase the risk of hepatotoxicity by increasing conversion of acetaminophen to toxic metabolites. Isoniazide also increases risk of acetaminophen hepatotoxicity. Acetaminophen may enhance the anticoagulant effect of warfarin with daily doses > 1.3 g for > 1 week. Phenothiazines may increase risk of severe hypothermia with acetaminophen. Cholestyramine resin may decrease the absorption of acetaminophen. 

Biological Activities and Analogues. Somatostatin exerts some neurotropic actions, eg, as a tranquilizer and as a spontaneous motor activity depressor. It also lengthens barbiturate anesthesia time and induces sedation and hypothermia. These actions are consistent with the strong association between somatostatin and GABA in the primate cerebral cortex, 90—95% of somatostatin-positive ceHs also contain GABA (100). 

CCK is found in the digestive tract and the central and peripheral nervous systems. In the brain, CCK coexists with DA. In the peripheral nervous system, the two principal physiological actions of CCK are stimulation of gaU. bladder contraction and pancreatic enzyme secretion. CCK also stimulates glucose and amino acid transport, protein and DNA synthesis, and pancreatic hormone secretion. In the CNS, CCK induces hypothermia, analgesia, hyperglycemia, stimulation of pituitary hormone release, and a decrease in exploratory behavior. The CCK family of neuropeptides has been impHcated in anxiety and panic disorders, psychoses, satiety, and gastric acid and pancreatic enzyme secretions. 

Cells are normally kept at osmotic (water activity) equilibrium by the action of the Na-pump. Inhibition of the pump with the specific Na -K -ATPase inhibitor, ouabain, causes cell swelling as does inhibition of it by hypothermia. The intracellular environment contains a high concentration of K (100 to 120 mM, in most mammalian cells), lower concentrations of Na (about 10 to 30 mM), and high... 

Death from overdose of barbiturates may occur and is more likely when more than 10 times the hypnotic dose is ingested. The barbiturates with high lipid solubility and short half-lives are the most toxic. Thus the lethal dose of phenobarbital is 6—10 g, whereas that of secobarbital, pentobarbital, or amo-barbital is 2-3 g. Symptoms of barbiturate poisoning include CNS depression, coma, depressed reflex activity, a positive Babinski reflex, contracted pupils (with hypoxia there may be paralytic dilation), altered respiration, hypothermia, depressed cardiac function, hypotension, shock, pulmonary complications, and renal failure. 

The Qxo, or temperature coefficient, is the factor by which the rate of a biologic process increases for a 10 °C increase in temperature. For the temperatures over which enzymes are stable, the rates of most biologic processes typically double for a 10 °C rise in temperature (Qjo = 2). Changes in the rates of enzyme-catalyzed reactions that accompany a rise or fall in body temperature constitute a prominent survival feature for cold-blooded life forms such as lizards or fish, whose body temperatures are dictated by the external environment. However, for mammals and other homeothermic organisms, changes in enzyme reaction rates with temperature assume physiologic importance only in circumstances such as fever or hypothermia. 

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. 

De Georgia et al. Stroke 2004 63 312-317 Prospective, randomized cooling vs. standard therapy for feasibility and safety 18 of40tx with hypothermia Hypothermia to 33°C with endovascular catheter on safety in pts with anterior circulation stroke and NIHSS >8 Similar clinical outcomes and lesion growth as measured on DWI MRI. Nonsignificant reduction in DWI volume in patients who cooled well. 

Schwab et al. Stroke 1999 30(5) 1153 Prospective pilot study moderate hypothermia in severe stroke and ICP 25 of 25 tx with hypothermia Hypothermia to 33-34°C with cooling blankets in pts with compete MCA infarct and ICP monitor 44% mortality, all by herniation after secondary rise in ICP after rewarming period. Good control of ICP during hypothermia period. Forty percent rate of pneumonia... 

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. 

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