Dorottya Kelen

Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia

Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia–ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry.

Experimental treatments for hypoxic ischaemic encephalopathy.

Hypoxic ischaemic encephalopathy continues to be a significant cause of death and disability worldwide. In the last 1-2 years, therapeutic hypothermia has entered clinical practice in industrialized countries and neuroprotection of the newborn has become a reality. The benefits and safety of cooling under intensive care settings have been shown consistently in trials; therapeutic hypothermia reduces death and neurological impairment at 18 months with a number needed to treat of approximately nine. Unfortunately, around half the infants who receive therapeutic hypothermia still have abnormal outcomes. Recent experimental data suggest that the addition of another agent to cooling may enhance overall protection either additively or synergistically. This review discusses agents such as inhaled xenon, N-acetylcysteine, melatonin, erythropoietin and anticonvulsants. The role of biomarkers to speed up clinical translation is discussed, in particular, the use of the cerebral magnetic resonance spectroscopy lactate/N-acetyl aspartate peak area ratios to provide early prognostic information. Finally, potential future therapies such as regeneration/repair and postconditioning are discussed.

Brain Cell Death Is Reduced With Cooling by 3.5°C to 5°C but Increased With Cooling by 8.5°C in a Piglet Asphyxia Model

Background and Purpose— In infants with moderate to severe neonatal encephalopathy, whole-body cooling at 33°C to 34°C for 72 hours is standard care with a number needed to treat to prevent a adverse outcome of 6 to 7. The precise brain temperature providing optimal neuroprotection is unknown. Methods— After a quantified global cerebral hypoxic-ischemic insult, 28 piglets aged <24 hours were randomized (each group, n=7) to (1) normothermia (38.5°C throughout) or whole-body cooling 2 to 26 hours after insult to (2) 35°C, (3) 33.5°C, or (4) 30°C. At 48 hours after hypoxia-ischemia, delayed cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and cleaved caspase 3) and microglial ramification (ionized calcium-binding adapter molecule 1) were evaluated. Results— At 48 hours after hypoxia-ischemia, substantial cerebral injury was found in the normothermia and 30°C hypothermia groups. However, with 35°C and 33.5°C cooling, a clear reduction in delayed cell death and microglial activation was observed in most brain regions (P<0.05), with no differences between 35°C and 33.5°C cooling groups. A protective pattern was observed, with U-shaped temperature dependence in delayed cell death in periventricular white matter, caudate nucleus, putamen, hippocampus, and thalamus. A microglial activation pattern was also seen, with inverted U-shaped temperature dependence in periventricular white matter, caudate nucleus, internal capsule, and hippocampus (all P<0.05). Conclusions— Cooling to 35°C (an absolute drop of 3.5°C as in therapeutic hypothermia protocols) or to 33.5°C provided protection in most brain regions after a cerebral hypoxic-ischemic insult in the newborn piglet. Although the relatively wide therapeutic range of a 3.5°C to 5°C drop in temperature reassured, overcooling (an 8.5°C drop) was clearly detrimental in some brain regions.

Systemic effects of whole-body cooling to 35, 33 and 30 deg c in a piglet model of perinatal asphxyia

Background Therapeutic hypothermia reduces neurological damage and improves survival in neonatal encephalopathy. Despite treatment, however, 50% infants have adverse outcomes. Clinical trials are investigating lower cooling temperatures as tailoring cooling may be beneficial. Objective To assess systemic effects of cooling to 35, 33 and 30°C in a piglet model of perinatal asphyxia. Design/methods 28 male piglets, <24 h, underwent hypoxia-ischaemia and randomized (groups n=7), with intervention from 2 to 26 h to (i) normothermia; (ii) hypothermia (35°C); (iii) hypothermia (33.5°C); intravenous) hypothermia (30°C). Heart rate (HR), mean arterial blood pressure (MABP) and rectal temperature (Trec) were recorded continuously; blood chemistry every 6 h. Results Five animals in the 30°C group died before 48 h due to cardiac arrest, no piglets died prematurely in other groups. During cooling, HR was similar at 30°C versus 35 and 33.5°C and MABP did not differ between groups. However, inotrope and volume replacement were higher at 30°C versus all other groups (p<0.001). Blood pH was lower at 12 and 24 h (p<0.001) at 30°C versus all other groups (figure 1A). Blood glucose, lactate and BE were abnormal at 24 h (all p< 0.05) at 30°C versus all other groups (figures 1B–D). Abstract 8B.2 Figure 1 Mean (SD) saline bolus and inotrope infusions over 48 h in the four groups. *p<0.001. Conclusions Cooling to 30°C required extensive cardiovascular support and led to significant metabolic derangement and more cardiac arrests. Despite similar MABP in all groups, systemic effects at 30°C were considerable and may be deleterious to the brain.