Post-asphyxial Encephalopathy Research Articles

Therapeutic hypothermia translates from ancient history in to practice.

Acute post-asphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a “dream revisited”. In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 years ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting approximately 6 h, only to die hours to days later after a “secondary” deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to mid-childhood.

The mechanisms and treatment of asphyxial encephalopathy

Acute post-asphyxial encephalopathy occurring around the time of birth remains a major cause of death and disability. The recent seminal insight that allows active neuroprotective treatment is that even after profound asphyxia (the “primary” phase), many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting approximately 6 h, only to die hours to days later after a “secondary” deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Although many of these secondary processes are potentially injurious, they appear to be primarily epiphenomena of the “execution” phase of cell death. Animal and human studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible but before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, has been associated with potent, long-lasting neuroprotection. Recent clinical trials show that while therapeutic hypothermia significantly reduces morbidity and mortality, many babies still die or survive with disabilities. The challenge for the future is to find ways of improving the effectiveness of treatment. In this review, we will dissect the known mechanisms of hypoxic-ischemic brain injury in relation to the known effects of hypothermic neuroprotection.

Unexpected collapse in apparently healthy newborns – a prospective national study of a missing cohort of neonatal deaths and near-death events

BackgroundSudden and unexpected postnatal collapse (SUPC) of a healthy newborn infant is a rare event, which carries a high risk of mortality and significant neurodisability in survivors. An underlying condition...

Hypothermia: a systematic review and meta-analysis of clinical trials

Hypothermia is a potential neuroprotective intervention to treat neonatal post-asphyxial (hypoxic-ischemic) encephalopathy (HIE). In this meta-analysis of 13 clinical trials published to date, therapeutic hypothermia was associated with a highly reproducible reduction in the risk of the combined outcome of mortality or moderate-to-severe neurodevelopmental disability in childhood. This improvement was internally consistent, as shown by significant reductions in the individual risk for death, moderate-to-severe neurodevelopmental disability, severe cerebral palsy, cognitive delay, and psychomotor delay. Patients in the hypothermia group had higher incidences of arrhythmia and thrombocytopenia; however, these were not clinically important. This analysis supports the use of hypothermia in reducing the risk of the mortality or moderate-to-severe neurodevelopmental disability in infants with moderate HIE.

Neonatal EEG-sleep disruption mimicking hypoxic-ischemic encephalopathy after intrapartum asphyxia

Objectives: EEG-sleep organization of asphyxiated and non-asphyxiated full-term neonates was compared during the first 3 days after birth. Background: Aggressive fetal and neonatal resuscitative efforts have reduced the severe expression of the neonatal brain disorder termed hypoxic-ischemic encephalopathy. Neonates may alternatively express altered EEG-sleep organization over the first days of life after asphyxia which may mimic mild or moderate hypoxic-ischemic encephalopathy. None of ten asphyxiated infants had EEG-confirmed seizures or pharmacologically-induced encephalopathies. All asphyxiated infants expressed fetal distress on fetal heart monitoring prior to delivery, and required neonatal resuscitation, as reflected in depressed 1, 5, and 10 min Apgar scores. Moderate to severe metabolic acidosis was also documented at birth in the asphyxiated group. All ten asphyxiated infants displayed either hyperalertness/irritability or somnolence/lethargy during the first 24 h after birth, suggesting mild to moderate post-asphyxial encephalopathy. Twenty-two 1 h 21-channel EEG polygraphic studies were obtained from the first through third days of life on nine asphyxiated infants and scored for EEG-sleep states. Studies on 23 non-asphyxiated newborns were also obtained between 1 and 3 days of life and scored for EEG-sleep state. EEG-sleep states were assigned to every minute of each record by visual analyses, without knowledge of the presence or absence of asphyxia. Comparisons of active, quiet, and indeterminate sleep percentages between neonatal groups were performed. Nested MANOVA was used which took into account multiple observations per child in the asphyxiated group. Results: The percent of active sleep was 44.7% (±14.7), the percent of quiet sleep was 38.7% (±14.3), and the percent of indeterminate sleep was 13.3% (±11.4) in the non-asphyxiated group. The percent of active sleep was 18.9% (±18.5), the percent of quiet sleep was 46.5% (±21.1), and the percent of indeterminate sleep was 33.4% (±19.7) in the asphyxiated group. A significant decrease in active sleep ( F=39.5, P<0.0001), and significant increases in quiet sleep ( F=4.6, P<0.05) and indeterminate sleep ( F=21.5, P<0.0005) were noted in the asphyxiated group. Shorter active sleep bout lengths were noted ( F=21.8, P<0.001), while the quiet sleep bout lengths remained unchanged for the asphyxiated group. Conclusions: An increased percentage of quiet sleep and indeterminate sleep at the expense of decreased active sleep reflects postnatal brain adaptation to asphyxia in infants despite the absence of overt clinical or electrographic evidence of hypoxic-ischemic encephalopathy. Brain adaptation in newborns after acute asphyxial stress may be expressed as altered sleep organization, despite clinical signs which may masquerade as mild to moderate post-asphyxial encephalopathy. EEG-sleep studies can assist in a more accurate classification of newborn encephalopathy that does not satisfy the criteria for hypoxic-ischemic encephalopathy.

The role of fetal ECG monitoring in labour

Routine electronic fetal heart rate monitoring has been associated with a significant reduction in fetal mortality and early onset neonatal seizures. However, the positive predictive value of changes in the fetal heart rate pattern is very low, and thus there has been a disproportionate increase in the rates of operative intervention in labour, compared with very modest reductions in neonatal encephalopathy. Recent studies have demonstrated that postasphyxial encephalopathy in term babies now derives almost entirely from low and medium risk pregnancies. This suggests that the current model of obstetric care is very effective in high-risk populations. However, further improvements in the care of what are now generally low risk patients will require simple, widely applicable strategies for detecting the infant at risk of asphyxial complications.

Postasphyxial encephalopathy in preterm neonates.

Perinatal asphyxia is an important determinant of infant neurological outcome. There are very few studies looking exclusively at postasphyxial encephalopathy in preterm neonates. We studied the neurologic and sonographic abnormalities in 40 preterm babies with severe birth asphyxia during their hospital stay and till 3 months corrected age. 87.5 % of the asphyxiated preterm babies had neonatal neurologic abnormality, compared to only 17% of the control babies (p<0.0001). Generalised hypotonia and reduced activity were the commonest abnormalities (observed in 85% of asphyxiated babies) while depressed sensorium (60%) and seizures (35%) were seen in more severe cases. White matter disease (WMD-including periventricular flare, cerebral edema and periventricular leucomalacia) was significantly more frequent in the study cases (34.5% in study cases vs 7.5% in controls, p<0.0001) as was grade 3/4 intraventricular hemorrhage(IVH) (25% in study cases vs 2.5% in controls, p<0.0001). There was 11 fold higher mortality among the asphyxiated babies (23 deaths in study cases vs 2 in controls, p<0.0001). The survivors had a significantly higher incidence of both mild and severe neurological abnormalities at corrected age of 3 months among the asphyxiated babies. There was a good correlation between the severity of the neonatal encephalopathy as well as the sonographic findings and the outcome.

Définition de l'asphyxie à la naissance et incidence des complications neurologiques et systémiques chez le nouveau-né à terme

In a prospective multicentric study, 152 of 10,065 live term births had birth asphyxia, defined by the association of three indicators (fetal distress, depression at birth and metabolic acidosis). The incidence of birth asphyxia was 1.5% of live term births when birth asphyxia was defined by the presence of at least two indicators, and 1% of live term births when birth asphyxia was defined by the association of metabolic acidosis and another indicator. Neurological complications were observed in 66 cases (43%). The incidence of post-asphyxial encephalopathy (PAE) was 5.9/1000 of live term births (mild PAE: 3/1000; moderate PAE: 2.7/1000; severe PAE: 0.2/1000). Systemic complications were observed in 87 patients (57%). Renal injury and coagulopathy were associated with moderate or severe PAE. Respiratory complications (39%), infections (17%) and gastro-intestinal intolerance (15%) often complicated the course. Severe complications were never seen in the absence of significant metabolic acidosis at 30 minutes of life. Our study has many implications concerning the diagnosis of birth asphyxia and its complications. A terminology based on clinical observation and arterial pH evaluation is proposed in order to clarify the situation.

Fetal arterial Doppler-IUGR and hypoxia

Vascular resistances of various fetal arreas are assessed by Doppler ultrasound. The PI, RI and S/D indices are measured on the cerebral, renal, aortic and umbilical Doppler spectrum. Ratios of these indices based on the comparison of the cerebral (Rc) and the umbilical (Rp) resistances, or carotid (Rcc) and umbilical resistances, or cerebral (Rc) and aortic (Rao) resistances (Rc.Rp or Rp/Rcc, or Rc/Rao), measure the flow redistribution between the placenta and brain. The umbilical resistance indices, when greater than the upper limit of the normal range (>2sd) are frequently associated with IUGR. (Sensitivity about 65 to 70%). Absent end diastolic flow is most of the time associated with severe IUGR and hypoxia and poor fetal outcome. A fairly good correlation was found between the existence of significantly decrerased (<.2sd) cerebral resistance and the development of post asphyxial encephalopathy in the neonate (Specificity 75% Sensitivity 87%). The earliest detectors of IUGR and hypoxia are the cerebral-umbilical cerebral-carotid, or cerebral-aortic ratios (Sensitivity 85% specificity 90%). When used as predictor of poor perinatal outcome in growth retarded fetuses, the cerebral umbilical ratio shows a sensitivity of 90% compared with 78% of the middle cerebral artery, and 83% for the umbilical artery indices. Changes of this ratio are well correlated with the fetal pO 2 changes. The renal flow response to hypoxia depends on the degree of hypoxia. Opposite responses were found in case of moderate, and severe IUGR or hypoxia. Thus, it is too early to conclude if the renal indices are reliable parameters for the evaluation of fetal hypoxia. The sensitivity in predicting IUGR was for the aortic PI: 41% and for the aortic BFC (Blood flow classes): 57%. In predicting delivery for fetal distress, the corresponding values were 76 and 87%, respectively. Because the resistance indices are heart rate-dependent, it is dangerous to draw any conclusion from one single value of any of these parameters. Only several successive measurement of the Doppler indices or of their ratio, may lead to a reliable evaluation of fetal hemodynamics. In the case of significant IUGR with abnormal Doppler indices it is recommended to repeat the Doppler measurements daily both at the cerebral and umbilical or aortic level in order to follow up the fetal flow redistribution which is highly correlated with the fetal pO 2 changes.

Incidence of post-asphyxial encephalopathy (PAE) in term neonates: a hypothesis of “precocious postmaturity” as a risk factor. 959

Background: The spectrum of recognized causes of PAE varies from pre-eclampsia to shoulder dystocia, but the incidence of these clear causes of PAE is not known. Objectives: (1)To determine the proportion of a cohort of term newborns with PAE in which a cause or risk factor can be clearly identified and (2) to generate hypotheses of causation in those with no recognizable causation or factors. Study design: A cohort of all term infants with PAE (ACOG) admitted to a regional level-III NICU for outborn infants, from 1990 to 1993 was retrospectively studied. Recognized causes and risk factors for asphyxia were identified. Causes were divided into three groups(1)Clear causes (eg. abruptio placentae);(2)Risk factors present (eg. oligohydramnios, cigarette smoking); (3) No causes or risk factors. Exclusion criteria: Haemorrhagic shock, septic shock & head trauma.

Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy.

The purpose of this study was to test the hypothesis that a high lactate signal and a low N-acetyl-aspartate/choline ratio in neonates with postasphyxial encephalopathy indicated a high chance of an adverse outcome in vivo when proton magnetic resonance spectroscopy was used. Twenty-one full-term asphyxiated neonates were examined at a mean postnatal age of 7.1 d. Five patients died, and five survivors had handicaps. Eleven of the 16 survivors (seven without handicaps and four with handicaps) had a second examination at 3 mo of age. After magnetic resonance imaging, spectra were obtained at 1.5 tesla. A 20-mm-thick slice was selected through the basal ganglia. After optimizing the B-0 field, we used a double spin-echo pulse sequence (90-180-180 degrees) with a time to repeat of 2000 ms and a time to echo of 272 ms. Two-dimensional spectroscopic imaging was performed by 32 x 32 phase encoding steps in two directions in a 225-mm field of view, resulting in 1-mL volumes, followed by computerized processing. Neuromotor development was examined at 6 wk, 3 mo, and every 3 mo thereafter. Lactate resonances were seen only in the five patients with grade 3 postasphyxial encephalopathy. Lactate was distributed diffusely (n = 4), or localized in areas of infarction (n = 1). N-acetyl-aspartate/choline ratios were significantly lower in the patients with an adverse outcome than in the survivors without handicaps, both neonatally (p < 0.005, Wilcoxon's rank sum test) and at 3 mo (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis of severe birth asphyxia and early prediction of neonatal neurological outcome in term asphyxiated newborns.

Ten indicators available during the first two hours of life, such as clinical criteria of neonatal distress and postnatal arterial blood gases, were compared with the neonatal neurological course in sixty full term newborns with significant birth asphyxia in order to test their value for the diagnosis and the short-term prognosis of severe birth asphyxia. Birth asphyxia was defined as severe when it was followed by symptoms of moderate or severe post-asphyxial encephalopathy. We calculated a sensitivity lower than fifty percent for clinical criteria such as delay in establishing regular respiration and Apgar scores. It was clear that normal delay in establishing regular respiration and normal Apgar scores do not exclude severe birth asphyxia. Arterial pH and base deficit at thirty minutes of life were found to be the best criteria for the diagnosis of severe birth asphyxia, but lacked positive predictive value. The best predictive tool for the short-term neurological prognosis of birth asphyxia was a single score established at 30 minutes of life and based on the evaluation of consciousness, respiration and neonatal reflexes. Some aspects of the pathophysiology of birth asphyxia and the rationale for treatment of post-asphyxial metabolic acidosis are discussed.

Somatosensory-Evoked Potentials in Term Neonates with Postasphyxial Encephalopathy

This article reviews the use of median nerve somatosensory-evoked potentials in full-term neonates with postasphyxial encephalopathy. The predictive value of this technique with regard to neurodevelopmental outcome is compared with that of clinical assessment and cranial ultrasonography.

Classification of Newborn Encephalopathy

Investigators from the Department of Neurology, Children’s Hospital and Harvard Medical School, Boston and the Neuroepidemiology Branch, Bethesda take issue with the terms hypoxic-ischemic and post-asphyxial encephalopathy when the etiology is frequently in doubt.

Creatine Kinase Isoenzyme BB Concentrations in the Cerebrospinal Fluid of Newborns: Relationship to Short-term Outcome

Creatine kinase brain isoenzyme (CK-BB) was determined in cerebrospinal fluid of 150 neonates by a newly developed immunoenzymatic assay. Newborns with a documented neurologic disorder (intraventricular hemorrhage, postasphyxial encephalopathy, central nervous system infection, or persistent periventricular intraparenchymal echodensities) showed markedly higher concentrations of immunoreactive CK-BB than did the normal newborns or those with subarachnoid hemorrhage. In neonates with seizures the data suggest that the underlying neurologic disorder accounts for the higher CK-BB values and not the seizures per se. High concentrations of CK-BB in the neonatal period were followed by poor short-term outcome.

57 EARLY PROGNOSIS OF POST-ASPHYXIAL ENCEPHALOPATHY IN TERM NEONATES: A CHALLENGE TO NEONATOLOGISTS

Nowadays, Intensive Care including hyperventilation makes difficult the clinical evaluation of asphyxiated term neonates. In order to precise the early prognosis of perinatal asphyxia, 35 fullterm neonates with moderate or severe post-asphyxial encephalopathy (Sarnat) were studied by means of ultrasonography (US), Doppler and electroencephalopathy (EEG). 18 infants died and the 17 survivors were prospectively followed-up. 4 developed a major handicap (cerebral palsy, seizures). Diffuse US echodensities, Resistance Index < 0.55, isoelectric, low voltage or paroxystic EEG's were considered as abnormal parameters in determing adverse outcome (death or severe handicap). The high sensitivities allow the clinician to have a high degree of confidence in sequential US, Doppler and EEG's in predicting bad outcome. The reasons for the differencies in specificities and positive predictive values will be discussed. (FNSRS no 32-25474.88).

Defective Regulation of Cerebral Oxygen Transport After Severe Birth Asphyxia

Cerebral artery Doppler ultrasonography was used to study the cerebral blood-flow velocity and cerebral oxygen transport of infants requiring a blood transfusion to correct anaemia. Mean flow velocity, pulsatility index and haemoglobin concentration were determined before and after transfusion. 11 stable preterm infants demonstrated an inverse relationship between haemoglobin concentration (or estimated arterial oxygen content) and mean flow velocity, indicating the presence of a homeostatic mechanism keeping brain oxygen transport within certain limits. Three infants with severe post-asphyxial encepalopathy had relatively high mean flow velocities and low pulsatility indices both before and after transfusion. There were no circulatory adjustments in response to an increase in haemoglobin concentration. Thus severe asphyxia at birth disrupted the homeostatic mechanism responsible for keeping brain oxygen transport constant. These findings stress the importance of close monitoring of arterial oxygen content, particularly for infants with severe post-asphyxial encephalopathy.

ANALYSIS OF CEREBROSPINAL FLUID (CSF) FROM NEONATES USING PROTON MAGNETIC RESONANCE SPECTROSCOPY (MRS)

Samples of CSF from 13 full-terra newborn infants were studied using high resolution proton MRS. CSF (0.5mls) was stored at -70°C, freeze-dried, reconstituted in deuterium oxide and a marker added for quantitation and chemical shift referencing. Spectra were obtained at 300 MHz, using presaturation to suppress the water signal. Ten samples were from neurologically normal infants. Spectra showed peaks attributed to lactate, acetate, citrate, glutamine, glucose, alanine, 3-hydroxybutyrate, creatine, formate and inositol. Spectra from the CSF of 3 infants with post-asphyxial encephalopathy and seizures showed a peak attributed to the drug carrier propylene glycol and another peak representing millimolar concentrations of unknown compound. Quantitative differences in the CSF spectra also occurred following asphyxia.Non-selective assay of multiple metabolites using proton MRS may help to define CSF markers of cerebral ischaemia which would be suitable for conventional analysis.

Severe birth asphyxia and abnormal cerebral blood-flow velocity.

Thirty-four fullterm infants with postasphyxial encephalopathy (PAE) were studied with ultrasound to assess cerebral blood-flow velocity (CBFV). A control group of 126 healthy infants also had CBFV recordings during the first week of life. Measurements for the majority of the asphyxiated group fell into two abnormal patterns in relation to the control group: four had low CBFV (less than 2 SD below the mean) and 17 had high CBFV (greater than or equal to 2 SD above the mean); all had severe PAE. Median age at the first high measurement was 26 hours. There were no statistically significant differences between infants with normal and abnormal CBFV in measurements of PaCO2 or mean arterial blood-pressure. A Pourcelot Resistance Index (PRI) less than 0.55 was common in the presence of high CBFV, but never seen with low measurements. 21 of the 34 infants died of their asphyxial insult and four of the survivors have severe cerebral palsy at a median age of two years. Three of the four with low CBFV died, and no infant with CBFV greater than 3 SD survived without severe impairment. The positive predictive value of CBFV measurements less than 2 SD or greater than 3 SD for death or severe impairment is 94 per cent, compared with 83 per cent for low PRI alone. The authors believe that high CBFV is the result of vasoparalysis of cerebral arterioles and that it represents a form of irreversible cerebral injury.

Prenatal cerebral Doppler ultrasonography and neonatal neurologic outcome.

The significance of fetal cerebral blood flow analysis in the prediction of neonatal neurologic outcome was investigated on 87 fetuses at risk for chronic hypoxia. Blood flow velocity waveforms were recorded from the fetal internal carotid artery immediately before cesarean section; newborns underwent neurologic follow-up until discharged from the neonatal division. Neonatal outcome was considered abnormal in presence of a postasphyxial encephalopathy. Receiver operating characteristic curves were used to demonstrate the efficacy of fetal cerebral blood flow velocity waveform analysis as a predictor of neonatal outcome. A value of the pulsatility index from the internal carotid artery below the second standard deviation of our range of normality was found to be a powerful indicator of the development of neonatal neurologic abnormalities (Cohen's Kappa index = .58). These results were particularly evident in fetuses with a birthweight above 2500 g in which a specificity of 93.7%, a sensitivity of 75%, and an accuracy of 89.7% were achieved.