Noninvasive monitoring of evolving urinary metabolic patterns in neonatal encephalopathy.

BACKGROUND: Infants with moderate and severe neonatal encephalopathy (NE) frequently suffer from long-term adverse outcomes. We hypothesize that the urinary metabolome of newborns with NE reflects the evolution of injury patterns observed with magnetic resonance imaging (MRI). METHODS: Eligible patients were newborn infants with perinatal asphyxia evolving to NE and qualifying for therapeutic hypothermia (TH) included in the HYPOTOP trial. MRI was employed for characterizing brain injury. Urine samples of 55 infants were collected before, during, and after TH. Metabolic profiles of samples were recorded employing three complementary mass spectrometry-based assays, and the alteration of detected metabolic features between groups was assessed. RESULTS: The longitudinal assessment revealed significant perturbations of the urinary metabolome. After 24 h of TH, a stable disease pattern evolved characterized by the alterations of 4-8% of metabolic features related to lipid metabolism, metabolism of cofactors and vitamins, glycan biosynthesis and metabolism, amino acid metabolism, and nucleotide metabolism. Characteristic metabolomic fingerprints were observed for different MRI injury patterns. CONCLUSIONS: This study shows the potential of urinary metabolic profiles for the noninvasive monitoring of brain injury of infants with NE during TH. IMPACT: A comprehensive approach for the study of the urinary metabolome was employed involving a semi-targeted capillary electrophoresis-time-of-flight mass spectrometry (TOFMS) assay, an untargeted ultra-performance liquid chromatography (UPLC)-quadrupole TOFMS assay, and a targeted UPLC-tandem MS-based method for the quantification of amino acids. The longitudinal study of the urinary metabolome identified dynamic metabolic changes between birth and until 96 h after the initiation of TH. The identification of altered metabolic pathways in newborns with pathologic MRI outcomes might offer the possibility of developing noninvasive monitoring approaches for personalized adjustment of the treatment and for supporting early outcome prediction.

Mineral Homeostasis and Effects on Bone Mineralization in the Preterm Neonate.

Most bone formation and mineralization occurs late in gestation. Accretion of adequate minerals is a key element of this process and is often interrupted through preterm birth. In utero, mineral transport is accomplished via active transport across the placenta and does not require fetal hormone input. Postnatal mineral homeostasis requires a balance of actions of parathyroid hormone, calcitonin, and vitamin D on target organs. Preterm birth, asphyxia, acidosis, and prolonged parenteral nutrition increase the risk of mineral imbalance and metabolic bone disease (MBD). Aggressive postnatal nutrition is key to preventing and treating MBD in preterm infants.

Trans-resveratrol enriched maternal diet protects the immature hippocampus from perinatal asphyxia in rats.

Trans-resveratrol (tRESV), a polyphenol with antioxidant properties, is common in many food sources, hence easily accessible for study as a maternal dietary supplement in perinatal asphyxia (PA). Hypoxic-ischemic encephalopathy secondary to PA affects especially vulnerable brain areas such as hippocampus and is a leading cause of neonatal morbidity. The purpose of this study is to identify new epigenetic mechanisms of brain inflammation and injury related to PA and to explore the benefit of tRESV enriched maternal diet. The hippocampal interleukin 1 beta (IL-1b), tumour necrosis factor alpha (TNFα) and S-100B protein, at 24-48h after 90min of asphyxia were assessed in postnatal day 6 rats whose mothers received either standard or tRESV enriched diet. The expression of non-coding microRNAs miR124, miR132, miR134, miR146 and miR15a as epigenetic markers of hippocampus response to PA was determined 24h post-asphyxia. Our results indicate that neural response to PA could be epigenetically controlled and that tRESV reduces asphyxia-related neuroinflammation and neural injury. Moreover, tRESV could increase, through epigenetic mechanisms, the tolerance to asphyxia, with possible impact on the neuronal maturation. Our data support the neuroprotective quality of tRESV when used as a supplement in the maternal diet on the offspring's outcome in PA.

Dietary interventions designed to protect the perinatal brain from hypoxic-ischemic encephalopathy--Creatine prophylaxis and the need for multi-organ protection.

Birth asphyxia or hypoxia arises from impaired placental gas exchange during labor and remains one of the leading causes of neonatal morbidity and mortality worldwide. It is a condition that can strike in pregnancies that have been uneventful until these final moments, and leads to fundamental loss of cellular energy reserves in the newborn. The cascade of metabolic changes that occurs in the brain at birth as a result of hypoxia can lead to significant damage that evolves over several hours and days, the severity of which can be ameliorated with therapeutic cerebral hypothermia. However, this treatment is only applied to a subset of newborns that meet strict inclusion criteria and is usually administered only in facilities with a high level of medical surveillance. Hence, a number of neuropharmacological interventions have been suggested as adjunct therapies to improve the efficacy of hypothermia, which alone improves survival of the post-hypoxic infant but does not altogether prevent adverse neurological outcomes. In this review we discuss the prospect of using creatine as a dietary supplement during pregnancy and nutritional intervention that can significantly decrease the risk of brain damage in the event of severe oxygen deprivation at birth. Because brain damage can also arise secondarily to compromise of other fetal organs (e.g., heart, diaphragm, kidney), and that compromise of mitochondrial function under hypoxic conditions may be a common mechanism leading to damage of these tissues, we present data suggesting that dietary creatine supplementation during pregnancy may be an effective prophylaxis that can protect the fetus from the multi-organ consequences of severe hypoxia at birth.

Ultrasound parameters and L/S ratio in prediction of perinatal outcome in term-growth restricted newborns.

AIM: The relation between biophysical profile (BPP), cerebroplacental (C/P) ratio, and lecithin/sphingomyelin (L/S) ratio as a predictor perinatal outcome in term intrauterine growth restricted (IUGR) neonates was evaluated. MATERIALS AND METHODS: A retrospective study of the perinatal outcome of 77 term monofetal pregnancies complicated with IUGR fetuses (< 10 percentile) who were terminated by cesarean section in 2010 was performed at the Institute of Gynecology and Obstetrics, Belgrade. RESULTS: The most frequent early neonatal complication was asphyxia. The authors found a strong correlation between the L/S ratio and birth weight (BW) r = 0.609, as well as between BPP and Apgar score 5 r = 0.583. Significant negative correlation was found between asphyxia and BPP r = -0.398, as well as between asphyxia and C/P ratio r = -0.379. CONCLUSION: In serous IUGR neonates, low values of BPP and L/S ratios predicted asphyxia.

Effect of high-dose phenobarbital on oxidative stress in perinatal asphyxia: an open label randomized controlled trial.

OBJECTIVE: To evaluate the effect of high dose phenobarbital on lipid peroxidation and antioxidant enzymes in perinatal asphyxia. DESIGN: Open label, Randomized controlled trial. SETTING: Neonatal intensive care unit of a tertiary care teaching hospital. PARTICIPANTS: 72 full term inborn neonates with severe birth asphyxia. METHODS: Neonates were randomized to Study (phenobarbital) group and Control group. The infants in the study group received phenobarbital infusion (40 mg/kg) within first two hours of life while babies in the control group did not receive any phenobarbital. Rest of the management in both the groups was as per the unit protocol for the management of hypoxic ischemic encephalopathy. A cerebrospinal fluid examination was done at 12 ± 2 hours of life to determine the levels of superoxide dismutase, glutathione peroxidise and malonyldialdehyde. 60 neonates were followed up at 1 month of age when a detailed neurological examination was done. RESULTS: Four neonates in the study group and six neonates in the control group died during the study. Two neonates in the study group were lost to follow up. The cerebrospinal fluid lipid peroxides and antioxidant enzymes were significantly lower in the phenobarbital group as compared to the control group. The neurological outcome at one month follow up was found to be comparable between the two groups. CONCLUSION: Phenobarbital (40 mg/kg) given in the first two hours of life in term neonates with perinatal asphyxia led to a decrease in CSF levels of lipid peroxides and antioxidant enzymes at 12 ± 2 hours of life.

Proton magnetic resonance spectroscopy in neonates with hypoxic-ischemic injury and its prognostic value.

It is difficult to predict the neurologic outcome of neonates with hypoxic-ischemic encephalopathy (HIE). Our goal was to investigate the prognostic values of magnetic resonance spectroscopy (MRS) in neonatal HIE. During this study, 46 neonates with HIE underwent magnetic resonance imaging (MRI) and proton MRS ((1)HMRS). The sample included 25 cases of mild HIE, 11 cases of moderate HIE, and 10 cases of severe HIE. Nine healthy neonates without asphyxia served as controls. (1)HMRS techniques included single-voxel MRS and 2-D-point-resolved spatially localized spectroscopy (PRESS) multivoxel chemical shift spectroscopy imaging. Then, 31 of 46 neonates with HIE were divided into 3 groups according to their prognosis: dead, abnormal, and normal outcome. Abnormal and normal outcome were defined by follow-up MRI. Metabolic changes were analyzed and compared with HIE grading and prognosis. As a result, the GLx-alpha peak was markedly increased in the moderate and severe HIE groups. The GLx-alpha/Cr ratio in the control, mild, moderate, and severe HIE groups was 0.18, 0.21, 0.64, 1.31, respectively. The Lac/Cr ratio was 0.12, 0.14, 0.19, and 0.26, respectively. A Spearman rank correlation test confirmed that the ratio of GLx-alpha/Cr and Lac/Cr had significant positive correlation with clinical grading of HIE (P < 0.01). The GLx-alpha/Cr ratio in the dead, abnormal, and normal outcome groups was 1.28, 0.82, and 0.25, respectively; the Lac/Cr ratio was 0.34, 0.19, and 0.14, respectively. An anaylsis of variance demonstrated that the differences were significant (both P < 0.01). A Spearman rank correlation test confirmed that the ratio of GLx-alpha/Cr and Lac/Cr had significant negative correlation with prognosis of HIE; GLx-alpha/Cr showed a much stronger correlation than the Lac/Cr ratio (P < 0.01). The formula of the relationship between the poor prognosis of HIE and the ratio of GLx-alpha/Cr in basal ganglia was established by the logistic regression model. In conclusion, (1)HMRS is a useful tool for evaluating the severity and prognosis of HIE. The higher ratio of GLx-alpha/Cr in the basal ganglia and thalamus may predict a poor outcome in neonates with HIE.

Astrocyte responses after neonatal ischemia: the yin and the yang.

Neonatal encephalopathy is a major predictor of neurodevelopmental disability in term infants and occurs in 1 to 6 of every 1,000 live term births. Despite improvements in perinatal practice during the past several decades, the incidence of cerebral palsy attributed to neonatal asphyxia remained essentially unchanged, primarily because management strategies were supportive and not targeted toward the processes of ongoing injury. Traditionally, experimental research in vivo focused on neurons, and more recently, oligodendrocytes whereas astrocytes have been more or less neglected. This review aims at dissecting possible protective as well as destructive roles of astrocytes in the immature ischemic brain to stimulate further research into this unexplored aspect of brain pathophysiology.

Prognostic value of 1H-MRS in neonatal encephalopathy.

The aim of this study was to determine the prognostic value of proton magnetic resonance spectroscopy in neonatal encephalopathy. Studies were carried out in 11 consecutive term newborns with encephalopathy probably caused by hypoxic-ischemic injury. The clinical evaluation included pregnancy data, labor conditions, encephalopathy grade, presence of seizures, and necessity of antiepileptic drug therapy. Polygraphic recordings were obtained in all cases. Interest areas evaluated by spectroscopy were the basal ganglia and thalami. Among the cases, N-acetylaspartate/creatine, choline/creatine, and lactate/creatine ratios were calculated and related to the clinical variables, polygraphic recordings, and 6-month neurodevelopmental outcome. Abnormal follow-up occurred in 5 of 11 patients (45.4%) and was clearly related to an Apgar score <5 at 5 minutes (P = 0.003), encephalopathy grade (P = 0.02), early neonatal seizures (P = 0.02), and antiepileptic therapy (P = 0.01). No relationship was observed between spectroscopy results and polygraphic recordings profile. The lowest mean N-acetylaspartate/creatine ratio was observed in four of five patients with an adverse outcome and, although not statistically significant, demonstrated a clear trend to unfavorable follow-up (t test = 0.06). The choline/creatine ratios could not be related to follow-up in our sample. The most consistently observed abnormality on the spectra was the presence of the lactate peak in four of five patients with unfavorable outcome, with a high relative risk to determine evolution in the sample, relative risk 7.0 (chi2 = 0.01, 95% confidence interval = 1.1-42.9).

A dose-response study of graded reoxygenation on the carotid haemodynamics, matrix metalloproteinase-2 activities and amino acid concentrations in the brain of asphyxiated newborn piglets.

PURPOSE: It is controversial to choose an appropriate oxygen concentration to resuscitate asphyxiated newborns regarding the clinical and biochemical oxidative effects. We examined the vasomotor response to reoxygenation with graded reoxygenation and the effects on matrix metalloproteinases and amino acids of the immature brain. METHODS: Thirty-two piglets (1-3 days, 1.5-2.1 kg) were instrumented for continuous monitoring of left common carotid and pulmonary arterial flows (Transonic). Piglets were randomized to a sham-operated control group (without hypoxia/reoxygenation) or 2 h hypoxia induced by decreasing the inspired oxygen concentration to 10-15%, followed by reoxygenation with 21, 50 or 100% oxygen for 1 h and then 21% oxygen for 3 h (n=8 each). The brains were then flash frozen and analyzed for matrix metalloproteinases and amino acid levels by zymography and HPLC, respectively. RESULTS: After 2 h oxygen deprivation, the absolute carotid flow remained similar but accounted for 38% of cardiac output (increased from 17% at baseline, p=0.001). During early reoxygenation, the flow rose in the piglets resuscitated with air (p<0.05), but not in those with supplemental oxygen. Carotid vascular resistance correlated significantly with the arterial partial pressure of oxygen (r=0.7). There was an oxygen-dependent increase in global cerebral activity of matrix metalloproteinase-2 with specific increases in the basal ganglia of all hypoxic-reoxygenated brains. There were no significant differences in glutamate and other amino acids in any brain regions. CONCLUSIONS: Although using high oxygen concentration to resuscitate asphyxiated newborn piglets increased carotid vascular resistance and cerebral matrix metalloproteinase-2 activity, there is no detrimental effect observed in this acute model of hypoxia-reoxygenation.

Effect of temperature on postanoxic, potentially neurotoxic changes of plasma pH and free iron level in newborn rats.

In asphyxiated newborns, iron, released from heme and ferritin and deposited in the brain, contributes to neurodegeneration. Because hypothermia provides neuroprotection, newborn mammals, showing reduced body temperature, might avoid iron-mediated neurotoxicity. However, hypothermia leads to acidosis, which induces hyperferremia. Therefore, we decided to study the effects of body temperature on plasma pH and iron levels in newborn rats exposed to a critical anoxia. Rectal temperature was kept at 33 degrees C (typical of neonates), reduced by 2 degrees C, or elevated to a level typical of healthy (37 degrees C) or febrile (39 degrees C) adults. Arterial blood samples were collected at 0, 10, 20, 30, and 120 min postanoxia. Control samples were obtained from normoxic, temperature-matched neonates. Anoxia tolerance time decreased progressively at rectal temperatures exceeding 33 degrees C. Neither pH nor plasma iron were significantly affected by anoxia at 33 degrees C. Although hypothermia (31 degrees C) resulted in acidosis in normoxic rats, both pH and iron levels were hardly influenced by anoxia. However, acidosis and hyperferremia, proportional to body temperature, developed at 37 and 39 degrees C. In conclusion, reduced body temperature is likely to protect asphyxiated newborns against iron-mediated brain injury.

Novel treatments after experimental brain injury.

Perinatal hypoxic-ischaemic encephalopathy(HIE) is being studied in laboratory models that allow the delayed cascade of events triggered by the energetic insult to be examined in detail. The concept of the 'excitotoxic cascade' provides a conceptual framework for thinking about the pathogenesis of HIE. Major events in the cascade triggered by hypoxia-ischaemia include overstimulation of N-methyl-D-aspartate type glutamate receptors, calcium entry into cells, activation of calcium-sensitive enzymes such as nitric oxide synthase, production of oxygen free radicals, injury to mitochondria, leading in turn to necrosis or apoptosis. New experimental approaches to salvaging brain tissue from the effects of HIE include inhibition of neuronal nitric oxide synthase, administration of neuronal growth factors, and inhibition of the caspase enzymes that execute apoptosis. Recent experimental work suggests that these approaches may be effective during a longer 'therapeutic window' after the insult, because they are acting on events that are relatively delayed. Application of modest hypothermia may allow these agents to be neuroprotective at even longer intervals after hypoxia-ischaemia.

Resuscitation with room-air or oxygen supplementation.

An accumulating body of data indicates that optimal newborn resuscitation is not performed with 100% oxygen. On the contrary, ambient air seems to have several advantages compared with supplemental oxygen. Present guidelines on newborn resuscitation should be critically reviewed and revised according to scientific evidence.

Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity.

OBJECTIVE: Free radical-induced postasphyxial reperfusion injury has been recognized as an important cause of brain tissue damage. We investigated the effect of high-dose allopurinol (ALLO; 40 mg/kg), a xanthine-oxidase inhibitor and free radical scavenger, on free radical status in severely asphyxiated newborns and on postasphyxial cerebral perfusion and electrical brain activity. METHODS: Free radical status was assessed by serial plasma determination of nonprotein-bound iron (microM), antioxidative capacity, and malondialdehyde (MDA; microM). Cerebral perfusion was investigated by monitoring changes in cerebral blood volume (delta CBV; mL/100 g brain tissue) with near infrared spectroscopy; electrocortical brain activity (ECBA) was assessed in microvolts by cerebral function monitor. Eleven infants received 40 mg/kg ALLO intravenously, and 11 infants served as controls (CONT). Plasma nonprotein-bound iron, antioxidative capacity, and MDA were measured before 4 hours, between 16 and 20 hours, and at the second and third days of age. Changes in CBV and ECBA were monitored between 4 and 8, 16 and 20, 58 and 62, and 104 and 110 hours of age. RESULTS: Six CONT and two ALLO infants died after neurologic deterioration. No toxic side effects of ALLO were detected. Nonprotein-bound iron (mean +/- SEM) in the CONT group showed an initial rise (18.7 +/- 4.6 microM to 21.3 +/- 3.4 microM) but dropped to 7.4 +/- 3.5 microM at day 3; in the ALLO group it dropped from 15.5 +/- 4.6 microM to 0 microM at day 3. Uric acid was significantly lower in ALLO-treated infants from 16 hours of life on. MDA remained stable in the ALLO group, but increased in the CONT group at 8 to 16 hours versus < 4 hours (mean +/- SEM; 0.83 +/- 0.31 microM vs 0.50 +/- 0.14 microM). During 4 to 8 hours, delta CBV-CONT showed a larger drop than delta CBV-ALLO from baseline. During the subsequent registrations CBV remained stable in both groups. ECBA-CONT decreased, but ECBA-ALLO remained stable during 4 to 8 hours of age. Neonates who died had the largest drops in CBV and ECBA. CONCLUSION: This study suggests a beneficial effect of ALLO treatment on free radical formation, CBV, and electrical brain activity, without toxic side effects.

Proton magnetic resonance spectroscopy of the brain in normal preterm and term infants, and early changes after perinatal hypoxia-ischemia.

The aims of this study were 1) to define normal perinatal maturational changes in proton metabolite peak-area ratios in two regions of the neonatal brain, the thalamic and occipitoparietal regions, and 2) to investigate abnormalities of these ratios after perinatal hypoxia-ischemia. Fifty-four infants were studied: 35 normal control infants at 31-42 wk of gestational plus postnatal age, and 19 "asphyxiated" infants suspected of cerebral hypoxic-ischemic injury. Proton spectra were collected at 2.4 tesla from (2 cm)3 voxels using the point-resolved spectroscopy technique with a 270-ms echo time. Lactate was detected in all infants studied. In the normal infants, lactate relative to N-acetylaspartate (NAA), choline and creatine was significantly greater in the occipitoparietal region than in the thalamus, and fell with increasing maturity in both regions, whereas NAA/ choline increased. The 19 asphyxiated infants were studied on a total of 34 occasions during the 1st wk of life (median age 1.8 d), at gestational plus postnatal ages of 27-41 wk. Maximum lactate/NAA was above 95% confidence limits for the control data in one or both regions in 11 of the 19 infants. Minimum NAA/choline was below 95% confidence limits in only one asphyxiated infants, who was later found to have congenital hypothyroidism. SD scores for lactate, relative to NAA, choline, and creatine, were higher in both regions in the asphyxiated infants compared with the normal infants, particularly in the thalamus. Early results of 1-y follow-up examinations indicate that raised lactate/NAA carries a poor long-term prognosis.

[Special aspects of carnitine in the neonatal period]. / Aspetti peculiari della carnitina nel periodo neonatale.

In view of the importance of L-Carnitine in neonatal metabolism, a study of 100 newborns aged between 33 and 40 weeks of gestation was carried out to determine the normal levels of total carnitine (CT), free carnitine (CL) and carnitine bound to acyl groups (AC), and to investigate any possible relationship between the above fractions and gestational age, type of nutrition and neonatal asphyxia. Suitable diets enriched with L-Carnitine, at a concentration of 1.04 mg/100 ml, included the administration of increasing amounts of milk formulas every 3rd hour, for a total of 7 times/day during the first week of life. Parenteral nutrition was given through an infusion pump during the early 48 hours of life; thereafter, the newborns were fed milk formulas enriched with L-Carnitine. It was observed that CT, CL and AC levels were significantly higher in newborns aged between 33 and 36 weeks of gestation than in older newborns. Nutrition with milk formulas enriched with L-Carnitine induced higher CT, CL and AC levels during the first week of life than on the first day of life. This increase is greater in newborns of more than 36 weeks of gestational age, with a significant difference from newborns of lower gestational age. Asphyxiated newborns showed a significantly higher CL concentration than non-asphyxiated newborns, while their AC values were lower than those found in control groups. In the post-natal period, the administration of milk formulas enriched with L-Carnitine is certainly beneficial for those metabolic processes in which L-Carnitine is involved.

Noninvasive assessment of cerebral oxidative metabolism in the human newborn.

Magnetic resonance spectroscopy (MRS) and near infrared spectroscopy (NIRS) permit direct observations within the human brain of a number of metabolites important in cerebral oxidative metabolism. MRS identifies high energy phosphorus metabolites such as phosphocreatine and ATP, which are products of oxidative phosphorylation and of the anaerobic accumulation of lactate. NIRS makes it possible to measure cerebral haemodynamics and oxygen delivery and to detect changes in the redox state of mitochondrial cytochrome oxidase. Studies in the brain of newborn infants after perinatal asphyxia have shown a delayed reduction in high energy phosphorus metabolites and an accumulation of lactate. Haemodynamic abnormalities frequently precede the delayed failure of energy metabolism. NIRS and MRS provide unique information on deranged cerebral energy metabolism following hypoxia-ischaemia and will guide the introduction of new cerebroprotective interventions.

Cerebral blood flow and metabolism during repeated asphyxias in newborn piglets: influence of theophylline.

The effect of theophylline on cerebral blood flow (CBF), oxygen transport, and energy metabolism was investigated during and following brief episodes of asphyxia. CBF was determined by microspheres during control, asphyxia, and recovery with reventilation after a single asphyxia (recovery I) and after 7 repeated asphyxias (recovery II). In addition, cerebral energy metabolism by 31P NMR spectroscopy and cerebral oxygen consumption (CMRO2) in newborn piglets treated with 30 mg/kg theophylline (serum levels 22-25 micrograms/ml) were compared with nontreated piglets. Theophylline increased CMRO2 during recovery I (348 mumol O2/min/100 g vs. 144 for non-theophylline) but not during control, asphyxia, or recovery II. There was no significant difference between the theophylline and non-theophylline groups in depletion of phosphoenergetics as measured by 31P NMR.

Global and depth resolved phosphorus magnetic resonance spectroscopy to predict outcome after birth asphyxia.

Twelve normal and 32 asphyxiated neonates were studied using global and depth resolved phosphorus magnetic resonance spectroscopy (31PMRS). Eight of the asphyxiated group died or survived with major neurodevelopmental abnormalities. A global phosphocreatinine/inorganic phosphate (PCr/Pi) ratio below the range of values from normal infants predicted adverse outcome after asphyxia with a positive predictive value of 64%, sensitivity 88%, and specificity 83%. Corresponding values for global inorganic orthophosphate/adenosine triphosphate (Pi/ATP) ratios were positive predictive value 88%, sensitivity 96%, and specificity 88%. Spatially localised MRS data, obtained using phase modulated rotating frame imaging, showed cerebral energy metabolism to be more abnormal in deep than superficial regions after birth asphyxia. However, in this population of full term infants none of the regional metabolite concentrations were superior to global data for prediction of outcome.

Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy.

To investigate the prognostic significance of abnormalities of oxidative phosphorylation, the brains of 61 newborn infants born at 27-42 wk of gestation and suspected of hypoxic-ischemic brain injury were examined by surface-coil phosphorus magnetic resonance spectroscopy. Of these infants, 23 died, and the neurodevelopmental status of the 38 survivors was assessed at 1 y of age. Of the 28 infants whose phosphocreatine/inorganic orthophosphate (PCr/Pi) ratios fell below 95% confidence limits for normal infants, 19 died, and of the nine survivors, seven had serious multiple impairments (sensitivity 74%, specificity 92%, positive predictive value for unfavorable outcome 93%). Of the 12 infants with ATP/total phosphorus ratios below 95% confidence limits 11 died (sensitivity 47%, specificity 97%, positive predictive value 91%). Among the 46 infants with increased cerebral echodensities, PCr/Pi was more likely to be low, and prognosis poor, in infants whose echodensities were diffuse or indicated intraparenchymal hemorrhage than in infants whose echodensities were consistent with periventricular leukomalacia. We conclude that when reduced values for PCr/Pi indicating severely impaired oxidative phosphorylation are found in the brains of infants suspected of hypoxic-ischemic injury, the prognosis for survival without serious multiple impairments is very poor, and that when ATP/total phosphorus is reduced, death is almost inevitable.