John S. Wyatt

Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial

BACKGROUND Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy. METHODS 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes. FINDINGS In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009). INTERPRETATION These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.

Estimation of optical pathlength through tissue from direct time of flight measurement.

Quantitation of near infrared spectroscopic data in a scattering medium such as tissue requires knowledge of the optical pathlength in the medium. This can now be estimated directly from the time of flight of picosecond length light pulses. Monte Carlo modelling of light pulses in tissue has shown that the mean value of the time dispersed light pulse correlates with the pathlength used in quantitative spectroscopic calculations. This result has been verified in a phantom material. Time of flight measurements of pathlength across the rat head give a pathlength of 5.3 +/- 0.3 times the head diameter.

Characterization of the near infrared absorption spectra of cytochrome aa3 and haemoglobin for the non-invasive monitoring of cerebral oxygenation

Near infrared (IR) spectroscopy can give continuous, direct information about cerebral oxygenation in vivo by providing signals from oxygenated and deoxygenated haemoglobin and cytochrome aa3. Due to a lack of precise spectral information and uncertainties about optical path length it has previously been impossible to quantify the data. We have therefore obtained the cytochrome aa3 spectrum in vivo from the brains of rats after replacing the blood with a fluorocarbon substitute. Near infrared haemoglobin spectra were also obtained, at various oxygenation levels, from cuvette studies of lysed human red blood cells. Estimates of optical path length have been obtained. The data were used to construct an algorithm for calculating the changes in oxygenated and deoxygenated haemoglobin and oxygenated cytochrome aa3 in tissue from changes in near IR absorption.

Quantification of cerebral oxygenation and haemodynamics in sick newborn infants by near infrared spectrophotometry.

New apparatus was made whereby indices of cerebral oxygenation and haemodynamics in sick newborn infants could be quantified by near infrared (NIR) spectrophotometry and displayed instantaneously at the cotside. The indices included oxygenated haemoglobin, reduced haemoglobin, oxidised cytochrome aa3, and total haemoglobin concentration: cerebral blood volume, mixed cerebral venous saturation, and changes in cerebral blood flow were then derived. Striking changes were observed in response to alterations in arterial oxygen saturation and carbon dioxide tension and to tilting of the infant. Abnormal responses were detected in cerebral oedema following birth asphyxia, patent ductus arteriosus, and cystic encephalomalacia. NIR spectrophotometry provides valuable quantitative data at the cotside for the management of sick infants and for exploring the pathophysiology of damage to the brain.

Experimentally Measured Optical Pathlengths for the Adult Head, Calf and Forearm and the Head of the Newborn Infant as a Function of Inter Optode Spacing

The Differential Pathlength Factor (DPF) has been measured for several different tissues. The results showed that the DPF varied with the type of tissue studied, and in the case of the adult calf with sex. However, the DPF for all tissues studied was constant once the inter optode spacing exceeded 2.5 cm. Thus, measurements can be made by NIR spectroscopy at a range of inter optode spacings, and a single DPF used in the calculation of chromophore concentration. The results also showed that the major source of error in the DPF lay in the measurement of the inter optode spacing. To improve accuracy, two options are possible. Firstly, some means of continuous measurement of inter optode spacing could be incorporated in the NIR instrumentation. The better alternative would be an instrument incorporating a method of directly measuring the optical pathlength at each wavelength. This could be done either by time of flight measurement, or if it can be validated, by phase shift measurement.

Methods of Quantitating Cerebral Near Infrared Spectroscopy Data

Non invasive infrared spectroscopy is a well established technique for monitoring changes in the oxygenation status of tissues (1). The technique has in particular been successfully employed to monitor changes in cerebral blood and tissue oxygenation by observing the absorption of haemoglobin and cytochrome aa3 respectively. Because of the highly light scattering nature of the tissues studied, it has normally not been possible to quantitate the observed changes.

Three-dimensional optical tomography of the premature infant brain

For the first time, three-dimensional images of the newborn infant brain have been generated using measurements of transmitted light. A 32-channel time-resolved imaging system was employed, and data were acquired using custom-made helmets which couple source fibres and detector bundles to the infant head. Images have been reconstructed using measurements of mean flight time relative to those acquired on a homogeneous reference phantom, and using a head-shaped 3D finite-element-based forward model with an external boundary constrained to match the measured positions of the sources and detectors. Results are presented for a premature infant with a cerebral haemorrhage predominantly located within the left ventricle. Images representing the distribution of absorption at 780 nm and 815 nm reveal an asymmetry consistent with the haemorrhage, and corresponding maps of blood volume and fractional oxygen saturation are generally within expected physiological values.

Determinants of outcomes after head cooling for neonatal encephalopathy

OBJECTIVE. The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy. METHODS. A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 ± 0.5°C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial). RESULTS. Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as ≥25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (≥38°C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy. CONCLUSIONS. Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.

Regional Hemodynamic Responses to Visual Stimulation in Awake Infants

This study presents the first measurements using near infrared spectroscopy of changes in regional hemodynamics as a response to a visual stimulus in awake infants. Ten infants aged 3 d to 14 wk viewed a checkerboard with a 5-Hz pattern reversal. The emitter and detector (optodes) of a near infrared spectrophotometer were placed over the occipital region of the head. Changes in concentration of oxy- and deoxyhemoglobin (Hbo2 and Hb) were measured and compared during 10-s epochs of stimulus on and off. A control group of 10 infants aged 18 d to 13 wk were examined with the same setup, but with the optodes over the frontoparietal region. In the test group the total hemoglobin concentration (Hbo2 + Hb) increased while the stimulus was on by a mean (±SD) of 2.51 (±1.48) μmol·L-1. Nine out of 10 infants showed an Hbo2 increase, and 9 out of 10 an Hb increase related to the stimulus. There was no significant change in any of these parameters in the control group. The results imply that there is increased cerebral blood flow due to stimulation that is specific to the visual cortex and that infants, unlike adults, show increased cerebral oxygen utilization during activation that outstrips this hemodynamic effect. The study demonstrates that near infrared spectroscopy can be used as a practical and noninvasive method of measuring visual functional activation and its hemodynamic correlates in the awake infant.

Effects of indomethacin on cerebral haemodynamics in very preterm infants

Near infrared spectroscopy was used to investigate the effects of intravenously administered indomethacin (0.1-0.2 mg/kg) on cerebral haemodynamics and oxygen delivery in 13 very preterm infants treated for patent ductus arteriosus. 7 infants received indomethacin by rapid injection (30 s) and 6 by slow infusion (20-30 min). In all the infants cerebral blood flow, oxygen delivery, blood volume, and the reactivity of blood volume to changes in arterial carbon dioxide tension fell sharply after indomethacin. There were no differences in the effects of rapid and slow infusion. These falls in cerebral oxygen delivery and the disruption of cerebrovascular control might compromise cellular oxygen availability, particularly in regions of the brain where the arterial supply is precarious. Care should be taken to ensure that oxygen delivery is optimum before the administration of indomethacin to preterm infants.