Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia

Abstract

Intra-ischemic moderate hypothermia generally protects the brain against ischemic cell death, while hypothermia instigated several hours into the reperfusion phase is considered to be less effective. Here we report the effect of hypothermia (32.5 degrees - 33.5 degrees C) of 5-h duration, initiated at 2, 6, 12, 24 and 36 h into the recirculation phase following 10 min of transient cerebral ischemia, on ischemic neuronal injury in the hippocampus and striatum of the rat. Hypothermia induced at 2 h, and 6 h postischemia reduces neuronal damage in the entire hippocampal CA1 region by approximately 50%. In the lateral CA1 region hypothermia induced at 12 h postischemia, significantly mitigates necrosis. When initiated at 2 h postischemia, but not later, protection was also observed in the striatum. Hypothermia induced 24 and 36 h postischemia was ineffective. A period of hypothermia of 5 h, initiated 2 h postischemia, was required for marked neuronal protection in the CA1 region, while 3.5-h hypothermia decreased neuronal damage by approximately 10% and 30 min hypothermia was ineffective. The clinical implications of the data are that extended period of hypothermia initiated long into the recovery phase following ischemia may prove beneficial. Hypothermia protects brain regions displaying rapid as well as delayed neuronal damage, and a minimal time of hypothermia is required for effective neuronal protection. Also, strict temperature control for up to 24 h postischemia may be required for proper assessment of the efficacy of cerebro-protective drugs.

Improved Neuroprotection with Hypothermia Delayed by 6 Hours Following Cerebral Hypoxia-Ischemia in the 14-Day-Old Rat

“…Postinsult hypothermia reduced infarct area, with longer periods of cooling providing progressively increased protection. Although this is in agreement with the results obtained in adult animals (25)(26)(27), studies using shorter periods of cooling in younger animals have shown contradictory results. Yager et al (18) observed no protection with postinsult hypothermia in the 7-d old rat; however, using the same model, Thoresen et al (28) found marked protection with 3 h of postinsult hypothermia.…”

Moderate Hypothermia in the Treatment of Patients With Severe Middle Cerebral Artery Infarction

“…[2][3][4][5][6] However, most of these studies used a narrow time window, with Applying these data to clinical practice would suggest that induced hypothermia is beneficial only in the very first few hours after stroke onset. Several neurosurgical studies showed a positive effect of mild hypothermia on uncontrollable intracranial hypertension after severe head trauma.…”

“…Sepsis as a systemic response to infection was suspected, according to the criteria of the American College of Chest Physicians, when Ն2 of the following conditions became manifest: heart rate Ͼ90 bpm, white blood cell count Ͼ12 000 or Ͻ4000 cells/mm 3 , respiratory rate Ͼ20 breaths per minute, or PaCO 2 Ͻ32 mm Hg. Body temperature as 1 further point was not analyzed.…”

“…1 In the past decade, it has come to be recognized that even mild (34°C to 36°C) or moderate (34°C to 28°C) therapeutic modulation of temperature may substantially avert brain damage caused by ischemia in both experimental stroke and other neuronal injuries. 2,3 After focal cerebral ischemia, hypothermia reduced infarct volumes up to 90%, 4 -6 whereas hyperthermia had a significantly negative effect on histopathological findings and outcome. [7][8][9] The mechanisms by which hypothermia is neuroprotective are not fully understood yet.…”

Systemic hypothermia to decrease morbidity of hypoxic-ischemic brain injury

“…In turn, the required threshold may be modified by the severity of the initial insult, how soon hypothermia is started after the insult and how long cooling is continued. 99,100,107 There is an obvious trade-off between the adverse systemic effects of cooling, which increase markedly below a core temperature of 32-341C, and the potential cerebral benefit. The potential systemic adverse effects of hypothermia in newborn infants include increased mortality particularly in preterm infant, hypoglycemia, reduction of cardiac contractility and cardiac output, ventilation-perfusion mismatch, increased blood viscosity, coagulopathy, acid-base and electrolyte imbalance and an increased risk of infections.…”