Phosphorus magnetic resonance spectroscopy 2 h after perinatal cerebral hypoxia-ischemia prognosticates outcome in the newborn piglet.

Phosphorus magnetic resonance spectroscopy ((31)P MRS) often reveals apparently normal brain metabolism in the first hours after intrapartum hypoxia-ischemia (HI) at a time when conventional clinical assessment of injury severity is problematic. We aimed to elucidate very-early, injury-severity biomarkers. Twenty-seven newborn piglets underwent cerebral HI: (31)P-MRS measures approximately 2 h after HI were compared between injury groups defined by secondary-energy-failure severity as quantified by the minimum nucleotide triphosphate (NTP) observed after 6 h. For severe and moderate injury versus baseline, [Pi]/[total exchangeable high-energy phosphate pool (EPP)] was increased (p < 0.001 and < 0.02, respectively), and [NTP]/[EPP] decreased (p < 0.03 and < 0.006, respectively): severe-injury [Pi]/[EPP] was also increased versus mild injury (p < 0.04). Mild-injury [phosphocreatine]/[EPP] was increased (p < 0.004). Severe-injury intracellular pH was alkaline versus baseline (p < 0.002). For severe and moderate injury [total Mg]/[ATP] (p < 0.0002 and < 0.02, respectively) and [free Mg] (p < 0.0001 and < 0.02, respectively) were increased versus baseline. [Pi]/[EPP], [phosphocreatine]/[Pi] and [NTP]/[EPP] correlated linearly with injury severity (p < 0.005, < 0.005 and < 0.02, respectively). Increased [Pi]/[EPP], intracellular pH and intracellular Mg approximately 2 h after intrapartum HI may prognosticate severe injury, whereas increased [phosphocreatine]/[EPP] may suggest mild damage. In vivo(31)P MRS may have potential to provide very-early prognosis in neonatal encephalopathy.

Supra- and sub-baseline phosphocreatine recovery in developing brain after transient hypoxia-ischaemia: relation to baseline energetics, insult severity and outcome.

Following hypoxia-ischaemia (HI), an early biomarker of insult severity is desirable to target neuroprotective therapies to patients most likely to benefit; currently there are no biomarkers within the 'latent phase' period before the establishment of secondary energy failure. Brief transient phosphocreatine (PCr) recovery overshoot (measured absolutely or relative to nucleotide triphosphate, NTP) following HI has been observed in cardiac and skeletal muscle; its significance however is unclear. To investigate cerebral PCr recovery levels after HI in relation to (i) baseline metabolism, (ii) insult severity, (iii) energy metabolism at recovery and (iv) subsequent metabolic derangement, cerebral NTP, PCr and inorganic phosphate (relative to the exchangeable high-energy phosphate pool) were measured serially in an in vivo model of perinatal asphyxial encephalopathy using phosphorus-31 magnetic resonance spectroscopy. Measures were compared either in all piglets or between 3 subgroups with no (n = 5, favourable outcome), moderate (n = 8, intermediate outcome) or severe (n = 5, unfavourable outcome) secondary energy failure at 24 h after HI. Maximum NTP, PCr and inorganic phosphate recoveries were observed 2-8 h after HI. Following resuscitation, in subjects with favourable outcome PCr recovered to higher than its baseline level (overshoot); in subjects with unfavourable outcome maximum PCr recovery was lower than baseline and lower than in subjects with favourable and intermediate outcomes. Recovery PCr correlated linearly and negatively with both acute insult severity and baseline PCr/NTP. These results suggest that recovery metabolism 2-8 h after HI may provide an early biomarker of injury severity. PCr recovery overshoot in the developing brain may indicate a protective response to HI leading to cell recovery, survival and protection against subsequent stress. In addition, baseline cerebral metabolism (PCr/NTP) may identify vulnerable infants prior to invasive surgery.

Greater hypoxia-induced cell death in prenatal brain after bacterial-endotoxin pretreatment is not because of enhanced cerebral energy depletion: a chicken embryo model of the intrapartum response to hypoxia and infection.

Infection is a risk factor for adult stroke and neonatal encephalopathy. We investigated whether exposure to bacterial endotoxin increases hypoxia-induced brain cell death and impairs cerebral metabolic compensatory responses to hypoxia. Prehatching chicken embryos (incubation day 19) were exposed to bacterial lipopolysaccharide (LPS) (3 mg Salmonella typhimurium LPS per egg) or hypoxia (4% ambient O(2) for 1 h), alone or in combination with LPS, followed 4 h later by hypoxia. Cerebral cell death and glial activation were assessed histologically. Further, chicken embryo brains were studied by magnetic resonance imaging (MRI) and spectroscopy (MRS) to assess haemodynamic and metabolic responses. In most brain areas, combined LPS/hypoxia resulted in a 30- to 100-fold increase in terminal deoxynucleotidyl transferase dUTP nick end labelling -positive cells, compared to control and single-insult groups. Glial activation correlated with the severity of cell death and was significantly greater in the combined-insult group (P<0.05). Hypoxia was associated with a 10-fold increase in lactate/N-acetyl-aspartate (NAA), an approximately 20% increase in total creatine/NAA, rapid decreases in T2 and T2(*), and a reduction in direction-averaged brain-water diffusion (D(av)) by approximately 15%. Liposaccharide pretreatment did not alter the magnitude or timing of these responses, but engendered baseline shifts (increased Cho/NAA, Cr/NAA, and Dav, and reduced T2(*)). In conclusion, LPS greatly increased hypoxia-induced brain damage in this model and induced changes in baseline haemodynamics and metabolism but did not affect the magnitude of the glycolytic response to hypoxia. The damage-enhancing effects of LPS are not because of additional energy depletion but because of a synergistic toxic component.