Gorm Greisen

European Consensus Guidelines on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants – 2010 Update

Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the updated recommendations of a European panel of expert neonatologists who had developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. These updated guidelines are based upon published evidence up to the end of 2009. Strong evidence exists for the role of a single course of antenatal steroids in RDS prevention, but the potential benefit and long-term safety of repeated courses are unclear. Many practices involved in preterm neonatal stabilisation at birth are not evidence-based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS, but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be lifesaving, but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure or nasal ventilation. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion.

SURFACTANT THERAPY AND NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE FOR NEWBORNS WITH RESPIRATORY DISTRESS SYNDROME. DANISH-SWEDISH MULTICENTER STUDY GROUP

BACKGROUND In southern Scandinavia most babies with respiratory distress syndrome are initially treated with nasal continuous positive airway pressure. We performed a multicenter trial to investigate whether the addition of a single dose of porcine surfactant administered during a short intubation before the occurrence of serious deterioration could reduce the subsequent need for mechanical ventilation. METHODS We randomly assigned 35 infants with moderate-to-severe respiratory distress syndrome to surfactant therapy (Curosurf, 200 mg per kilogram of body weight) plus nasal continuous positive airway pressure and 33 infants to nasal continuous positive airway pressure alone. The study was not blinded. The indications for mechanical ventilation were a ratio of arterial to alveolar oxygen tension of less than 0.15, severe apneic attacks, or both. RESULTS Six hours after randomization, when the median age of the babies was 18 hours, the mean ratio of arterial to alveolar oxygen tension was 0.37 in the surfactant-treated babies, as compared with 0.25 in the controls (P < 0.001). The need for subsequent mechanical ventilation was reduced with surfactant therapy (to 43 percent of the surfactant-treated babies as compared with 85 percent of the controls; P = 0.003). When 17 infants with ratios of arterial-to-alveolar oxygen tension of less than 0.15 at randomization were excluded, the need for mechanical ventilation was still significantly reduced in the surfactant-treated group (to 33 percent [9 of 27 babies], as compared with 83 percent [20 of 24 babies] in the control group; (P < 0.001). After 28 days, two of the surfactant-treated babies had died, as compared with five of the control babies. CONCLUSIONS In babies with moderate-to-severe respiratory distress syndrome treated with nasal continuous positive airway pressure, a single dose of surfactant reduced the need for subsequent mechanical ventilation.

Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation

The reaction of cerebral blood flow to acute changes in arterial carbon dioxide pressure (PaCO2) and mean arterial blood pressure was determined in 57 preterm infants supported by mechanical ventilation (mean gestational age 30.1 weeks) during the first 48 hours of life. All infants had normal brain sonograms at the time of the investigation. In each infant, global cerebral blood flow was determined by xenon-133 clearance two to five times within a few hours at different levels of PaCO2. Changes in PaCO2 followed adjustments of the ventilator settings. Arterial oxygen pressure was intended to be kept constant, and mean arterial blood pressure fluctuated spontaneously between measurements. The data were analyzed by stepwise multiple regression, with changes in global cerebral blood flow, PaCO2, mean arterial blood pressure, and postnatal age or intracranial hemorrhage used as variables. In infants with persistently normal brain sonograms, the global cerebral blood flow-carbon dioxide reactivity was markedly lower during the first day of life (mean 11.2% to 11.8%/kPa PaCO2) compared with the second day of life (mean 32.6/kPa PaCO2), and pressure-flow autoregulation was preserved. Similarly, global cerebral blood flow-carbon dioxide reactivity and pressure-flow autoregulation were present in infants in whom mild intracranial hemorrhage developed after the study. In contrast, global cerebral blood flow reactivity to changes in PaCO2 and mean arterial blood pressure was absent in infants in whom ultrasonographic signs of severe intracranial hemorrhage subsequently developed. These infants also had about 20% lower global cerebral blood flow before hemorrhage, in comparison with infants whose sonograms were normal, a finding that suggests functional disturbances of cerebral blood flow regulation. Several perinatal factors were tested, but only birth after abruptio placentae was related to subsequent periventricular hemorrhage (p = 0.037).

Vasoparalysis associated with brain damage in asphyxiated term infants

The relationship of cerebral blood flow to acute changes in arterial carbon dioxide and mean arterial blood pressure (MABP) was determined during the first day of life in 19 severely asphyxiated term infants supported by mechanical ventilation. For comparison, 12 infants without perinatal asphyxia were also investigated. Global cerebral blood flow (CBF infinity) was determined by xenon 133 clearance two or three times within approximately 2 hours. During the cerebral blood flow measurement, the amplitude-integrated electroencephalogram and visual-evoked potential were recorded. Changes in arterial carbon dioxide pressure followed adjustments of the ventilator settings, whereas MABP fluctuated spontaneously. Arterial oxygen pressure and blood glucose concentration were in the normal range. Five of the asphyxiated infants had isoelectric electroencephalograms and died subsequently with severe brain damage. They had a high CBF infinity (mean 30.6 ml/100 gm/min) and abolished carbon dioxide and MABP reactivity. Lower CBF infinity (mean 14.7 ml/100 gm/min) and abolished MABP reactivity were found in another five asphyxiated infants with burst-suppression electroencephalograms in whom computed tomographic or clinical signs of brain lesions developed. The carbon dioxide reactivity was preserved in these infants. In the remaining nine asphyxiated infants without signs of central nervous system abnormality, carbon dioxide and MABP reactivity were preserved, as was also the case in the control group. We conclude that abolished autoregulation is associated with cerebral damage in asphyxiated infants and that the combination of isoelectric electroencephalograms and cerebral hyperperfusion is an early indicator of very severe brain damage.

Cerebral blood flow in the newborn infant: Comparison of Doppler ultrasound and 133xenon clearance

Two techniques of Doppler ultrasound examination, continuous-wave and range-gated, applied to the anterior cerebral artery and to the internal carotid artery, were compared with 133xenon clearance after intravenous injection. Thirty-two sets of measurements were obtained in 16 newborn infants. The pulsatility index, the mean flow velocity, and the end-diastolic flow velocity were read from the Doppler recordings. Mean cerebral blood flow was estimated from the 133Xe clearance curves. The correlation coefficients between the Doppler and the 133Xe measurements ranged from 0.41 to 0.82. In the subset of 16 first measurements in each infant, there were no statistically significant differences between the correlation coefficients of the various Doppler ultrasound variables, but the correlation coefficients were consistently lower for the pulsatility index than for mean flow velocity or end-diastolic flow velocity, and they were consistently higher for the range-gated than for the continuous-wave Doppler technique.

Carbon dioxide-related changes in cerebral blood volume and cerebral blood flow in mechanically ventilated preterm neonates : comparison of near infrared spectrophotometry and 133Xenon clearance

ABSTRACT: Carbon dioxide-induced changes in near infrared spectrophotometry recordings were compared with changes in cerebral blood flow estimated by 133Xenon clearance (global cerebral blood flow (infinity)) at serial measurements in 24 mechanically ventilated preterm infants (mean gestational age 30.2 wk). In all infants, three measurements were taken at different arterial carbon dioxide tension levels (mean 4.4 kPa, range 2.1-7.8) obtained by adjustment of the ventilator settings. Mean arterial blood pressure changed spontaneously, whereas arterial oxygen tension was kept within normal range. At all wavelengths (904, 845, 805, and 775 nm), the OD increased at higher arterial carbon dioxide tension levels, indicating cerebral vasodilation. This conclusion was supported by conversion of the data to changes in oxygenated and deoxygenated Hb concentration. A parallel increase in cerebral blood volume index and global cerebral blood flow (infinity) was found (P < 0.0001). The oxygenation level of cytochrome aa3 increased with increases in oxygen delivery (P < 0.0001). This observation, however, may have been artifactual due to cross-talk between the oxidized cytochrome aa3 and the oxygenated Hb signals, as these signals were closely interrelated in the present experimental design. We suggest that near infrared spectrophotometry may be used for estimation of the cerebral blood volume index/cerebral blood flow-CO2 reactivity within a wide range of arterial carbon dioxide tension. Knowledge of the light path length would put this estimation on a quantitative basis.

Estimating cerebral blood flow in newborn infants: comparison of near infrared spectroscopy and 133Xe clearance.

ABSTRACT: A new method of measuring cerebral blood flow (CBF) in newborn infants by means of near infrared spectroscopy (CBFnirs) was compared with the i.v. 133Xe clearance technique (CBFxe). Forty CBFnirs measurements were obtained during 19 133Xe measurements in 16 infants; 79 other CBFnirs data sets were discarded because the assumptions for their use were not fulfilled. The test-retest variation or repeated near infrared-measurements during each 133Xe clearance was 17.5%. CBFnirs was closely related to CBFxe (r2 = 0.84, p < 0.0001), with a slope of 0.75 (SEM = 0.064) and a intercept of 1.58 mL/100 g/min (SEM = 0.51). The difference between the measurements obtained by the two methods (CBFnirs – CBFxe) was negative in the high range of CBF, whereas the difference was close to zero in the low range. We conclude that CBF measured with near infrared spectroscopy was in good agreement with the CBF measured with the 133Xe method. The near infrared spectroscopy method has the advantage of being noninvasive, and it does not involve ionizing radiation. Because of methodologic constraints, however, it may underestimate CBF in the high range of flow, and it may have limitations of application in clinical research. (Pediatr Res 30: 570–573, 1991)

Cerebral blood flow in preterm infants during the first week of life.

ABSTRACT. Forty‐two preterm infants of 28–33 weeks of gestation were studied once during the first week of life by 133‐Xenon clearance after intravenous injection to estimate global cerebral blood flow. Count rates detected over the chest were corrected for chest wall contribution and used as arterial input function. A neonatal blood‐brain partition coefficient of Xenon was used for the calculation of a mean flow estimator (CBF‐∞). The techique was internally validated by use of differently obtained arterial input functions. In 11 infants wihout respiratory distress, CBF‐∞ was 19.8 ml/100 g/min ±5.3 SD. In 24 infants treated with mechanical ventilation CBF‐∞ was 11.8 ml/100 g/min ±3.2 SD. In 7 infants treated with continous positive airway pressure CBF‐∞ was 21.3 ml/100 g/min ±12.0 SD. When the reduction of CBF‐∞ associated with mechanical ventilation was taken into account, the 9 infants with subependymal/intraventricular haemorrhage had increased CBF‐∞. The effects of gestational age, birthweight, mode of delivery, postnatal age, mean arterial blood pressure, PaCO2, blood haemoglobin and phenobarbitone medication were also analysed and found inconsistent. In conclusion, CBF was lower than expected and in infants requring mechanical ventilation the values were lower still.

European consensus guidelines on the management of neonatal respiratory distress syndrome

Abstract Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the recommendations of a European panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is not clear if repeated courses are safe. Many practices involved in preterm neonatal stabilization at birth are not evidence based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be life saving but can cause lung injury, and protocols should be directed to avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure. For babies with RDS to have the best outcome, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate blood pressure.

Cerebral blood flow, PaCO2 changes, and visual evoked potentials in mechanically ventilated, preterm infants

ABSTRACT. Two estimations of global cerebral blood flow (CBF) using 133‐Xenon clearance were done with an interval of about one hour in 16 mechanically ventilated, newborn infants, of less than 33 weeks gestational age. In eight infants CBF was estimated just before a change in ventilator settings, and again when the Paco2 was stable. In the remaining eight infants small spontaneous changes in Paco2 occurred. The CBF‐CO2 reactivity was similar in the two groups (+67%/kPa (95% confidence interval 13–146) and 52%/kPa (24–86)) and considerably higher than the CBF‐CO2 reactivity estimated from the interindividual variation of flow and Paco2 (+19%/kPa (4–36)). There were no significant relations between CBF and arterial blood pressure. Flash evoked potentials (VEP) were recorded during the 133‐Xenon clearances in 8 of the infants. VEP showed no relation to changes in CBF, even when the blood flow rose from the lowest levels. CBF and VEP were obtained once in 9 other infants. Among the 17 infants, the latency of the first negative wave of the VEP was not related to the CBF level. Mean CBF in the 25 infants was 12.3 ml/100 g/min (range 4.3 to 18.9), mean Paco2 was 4.2 kPa (range 2.3 to 6.4). Thus, CBF‐CO2 reactivity appeared to be normal in these clinically stable, mechanically ventilated, preterm infants, suggesting that their low cerebral blood flow was well regulated. The absence of a relation of CBF with VEP suggested that cerebral blood flow was not critically decreased.