Impaired brain growth and neurodevelopment in preterm infants with posthaemorrhagic ventricular dilatation

Aim: To correlate volumetric magnetic resonance imaging at term with neurodevelopmental outcome at 2 years in infants with posthaemorrhagic ventricular dilatation. Preterm infants with posthaemorrhagic ventricular dilatation have high risk of disabilities, but the range is wide and predicting severity of motor and mental disability is difficult. Methods: Twenty‐five preterm infants with posthaemorrhagic ventricular dilatation had cerebral magnetic resonance imaging at term age. Total and regional brain volumes were calculated using a manual segmentation technique. Bayley Scales of Infant Development II were assessed at 2 years post‐term. Developmental Quotients (DQ) were calculated from Developmental Age Equivalent scores. Results: Total cerebral volume, excluding ventricles, correlated positively with Motor (r = 0.7, p < 0.0001) and Mental DQ (r = 0.4, p = 0.02). Only three of 16 infants with cerebral volume <336 cm³ were ambulant at 2 years. Cerebellar volumes correlated strongly with Motor DQ (r = 0.6, p = 0.002) but only with Mental DQ after adjustment. Thalamic volumes correlated strongly with Motor DQ (r = 0.7, p = 0.0002). Conclusion: Brain growth is significantly impaired in posthaemorrhagic ventricular dilatation. Volumetric measurements at term of total cerebral and cerebellar volume may have a role in predicting severity of disability.     

Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation

Posthemorrhagic ventricular dilatation (PHVD) is closely associated with white matter injury and neurologic disability in the preterm infant. An important factor in periventricular white matter damage may be the specific vulnerability of iron-rich immature oligodendroglia to reactive oxygen species toxicity. Non-protein-bound iron (NPBI) is a potent catalyst in the generation of hydroxyl radicals (Fenton reaction). Our objective was to determine whether NPBI is increased in cerebrospinal fluid (CSF) from preterm infants with PHVD compared with preterm control infants. Samples of CSF were obtained from 20 infants with PHVD and 10 control subjects. The level of NPBI was determined by a new spectrophotometric method using bathophenanthroline as a chelator. To evaluate the effect of hemolysis, CSF and blood were mixed in different proportions, spun, frozen and thawed, and then analyzed for NPBI. NPBI was found in 75% (15 of 20) of infants with PHVD and in 0% (0 of 10) of control infants (p = 0.0002). Hemolysis induced in vitro did not result in any significant levels of NPBI. Within the group with PHVD, NPBI concentrations in CSF did not correlate with disability, parenchymal brain lesions, or the need for shunt surgery. NPBI was increased in CSF from preterm infants with PHVD, and the increase could not be explained by hemolysis alone. Free iron may help to explain the association between intraventricular hemorrhage and white matter damage.     

Intraventricular streptokinase increases cerebrospinal fluid D dimer in preterm infants with posthaemorrhagie ventricular dilatation

Failure to lyse multiple small blood clots in the cerebrospinal fluid (CSF) reabsorption pathways may be one of the mechanisms leading to posthaemorrhagie ventricular dilatation (PHVD). It has been suggested that intraventricular administration of streptokinase may resolve PHVD but it is not known whether such treatment produces an increase in fibrin degradation products in the CSF. Ventricular CSF was collected from six infants with PHVD before and during intraventricular treatment with streptokinase 1000 units/h. In all six infants, CSF D dimer increased during streptokinase treatment. Median D dimer before treatment was 1642 μg/1 and during treatment 5440 μg/1 ( p < 0.05). Undetectable D dimer levels in plasma during streptokinase treatment ruled out the possibility that D dimer had merely diffused into the CSF. This augmentation of local fibrinolysis may have therapeutic potential. There was no evidence of systemic fibrinolysis.     

Intracranial pressure and cerebral blood flow velocity in preterm infants with posthaemorrhagic ventricular dilatation

AIM: To determine the volume of cerebrospinal fluid (CSF) that should be tapped in preterm infants with posthaemorrhagic ventricular dilatation as guided by intracranial pressure (ICP) and cerebral blood flow velocity (CBFV). METHODS: The total number of measurements was 106 in 22 infants. Birth weights ranged from 630 to 2050 g, gestational age from 24.5 to 30.3 weeks, and age at insertion from 12 to 67 days. A subcutaneous ventricular catheter reservoir for repetitive CSF drainage was placed when the diameter of a ventricle was > 4 mm above the 97th centile. A volume of 5 ml/kg body weight was removed twice daily. ICP and CBFV were determined before and after CSF tapping. RESULTS: If the ICP after tapping exceeded 7 cm H(2)O, tapping did not result in a significant improvement in CBFV. If the ICP before tapping was less than 6 cm H(2)O, tapping also had no effect on CBFV. Longitudinal studies in individual infants showed a slight correlation between ICP and CBFV. CONCLUSION: Volume of repetitive CSF drainage in preterm infants with posthaemorrhagic ventricular dilatation guided by ICP and CBFV may be a useful technique. An ICP of about 6 cm H(2)O is the cut off point for CSF drainage.     

早产儿脑损伤的相关因素分析

目的 分析早产儿脑损伤的影响因素.方法 对2006年1月至2007年10月我院收治的出生时胎龄小于36周的268例早产儿在生后7 d内行头部B超检查.并分析相关临床资料.结果 130例早产儿存在脑损伤,脑损伤的发生率为48.5%,其中脑室出血116例,发生率为43.3%,脑室周围日质软化38例,占14.2%.轻度和重度脑损伤发生率分别为23.5%、13.6%.脑损伤发生与下列因素有关:胎龄小、低出生体质量、窒息、肺透明膜病、呼吸暂停、呼吸衰竭、肺出血、低血糖、感染、低血压、凝血异常、胎膜早破以及宫内感染.结论 脑室出血以及脑室周围白质软化在早产儿中比较常见,其发生与多种因素有关.临床上应避免或治疗引起脑损伤的因素,头部B超可对早产儿脑损伤做出早期诊断.     

连续腰穿对重度脑室内出血早产儿脑脊液中非蛋白结合Fe2+和丙二醛水平的影响

目的 探讨连续腰穿对重度脑室内出血(IVH)早产儿脑脊液中非蛋白结合Fe2+和丙二醛(MDA)水平的影响.方法 对20例重度IVH早产儿行连续腰穿治疗,检测首次和末次腰穿脑脊液标本中的非蛋白结合Fe2+和MDA水平,20例对照组早产儿在生后7～14 d内只取一次脑脊液标本.结果 重度IVH组首次腰穿脑脊液中非蛋白结合Fe2+水平[(0.66±0.38) μmol/L]较对照组[(0.24±0.12) μmol/L]高,MDA水平[(1.21±0.41) μmol/L]亦较对照组[(0.89±0.35) μmol/L]高,差异均有显著性(P<0.01,P<0.05);重度IVH伴出血后脑室扩张(PHVD)者在首次和末次腰穿脑脊液中非蛋白结合Fe2+水平[(0.75±0.34) μmol/L、(0.57±0.21) μmol/L]均较未发生PHVD者[(0.54±0.31) μmol/L、(0.35±0.18) μmol/L]升高,差异有显著性(P<0.05),而MDA水平两者差异无显著性;两者在末次腰穿时脑脊液非蛋白结合Fe2+水平均较首次腰穿时降低,差异有显著性(P<0.05),而MDA水平无明显变化.结论 重度IVH早产儿脑脊液中非蛋白结合Fe2+和MDA水平升高,可能与Fe2+和氧自由基参与早产儿脑白质损伤有关,连续腰穿治疗可以降低脑脊液中非蛋白结合Fe2+水平.     

Developmental change of amplitude-integrated electroencephalographic activity in preterm infants with intraventricular hemorrhage

Background

Amplitude-integrated electroencephalography (aEEG) allows continuous brain function monitoring at bedside.

Objectives

This prospective cohort study was designed to longitudinally evaluate aEEG tracings at increased postmenstrual age (PMA) in preterm infants with intraventricular hemorrhage (IVH).

Methods

Biweekly aEEG recordings were performed on preterm infants < 32 weeks gestational age from 24 to 36 weeks PMA. The tracings were evaluated according to a scoring system adapted from Burdjalov et al.

Results

We analyzed 496 aEEG recordings in 105 preterm infants. The control group consisted of 42 infants with no IVH, whereas the IVH grade I, II, III, and IV groups consisted of 38, 8, 3, and 14 infants, respectively. There were significant differences in the cycling and total maturation scores among the IVH groups at 36 weeks PMA (p = 0.010 and p = 0.006, respectively). The IVH-IV patients maintained low scores in their cycling as their PMA increased, in contrast to their continuity and amplitude scores. The risk factors affecting the aEEG maturation scores at 36 weeks PMA in the IVH-IV patients included seizure events with the administration of antiepileptic drugs and the insertion of external ventricular drains (β = − 0.679 and β = − 0.418, respectively; p = 0.003).

Conclusions

The low cycling scores persisted until 36 weeks PMA in the IVH-IV group.     

Correlation of grading and duration of periventricular echodensities with neurodevelopmental outcome in preterm infants

Background Transient periventricular echodensities (PVE) in preterm infants affect neurodevelopmental outcome.Objective To correlate the duration and grading of PVE with neurodevelopmental outcome.Materials and methods A retrospective, single-centre cohort study of infants with PVE diagnosed by ultrasonography from 1995 to 2000 with blinded grading and recognition of duration of PVE.Results A total of 72 infants (median gestational age 32 weeks, median birth weight 1,668 g) were diagnosed as having PVE. Minor neurological abnormalities were diagnosed in seven (10%), cerebral palsy in six (8%), developmental delay in seven (10%), and mild mental retardation in two (3%) of the infants. Differences regarding adverse outcome were not significant between infants with severity grade 1 compared to severity grade 2 (16% and 22%, respectively). There was a significant increase in adverse neurodevelopmental outcome with increasing duration of PVE. Of 33 infants with duration of PVE <7 days, 1 (3%) had an adverse neurodevelopmental outcome, compared to 6 (24%) of 25 infants with a duration of PVE of 7–14 days, and 6 (43%) of 14 infants with a duration of PVE >14 days (P<0.002, RR 7.920, 95% CI 1.017–61.661; P<0.001, RR 14.143, 95% CI 1.871–106.895, respectively).Conclusion The duration, but not the grading, of transient PVE was significantly correlated with neurodevelopmental outcome.     

Postnatal urinary conductance measurement in preterm infants

The aim of this study was to determine whether serial urinary conductance measurements can be used to estimate reliably the end of the transition period of negative sodium balance in preterm infants. The relationship between urine conductance, measured by a conductance meter, and urine sodium concentration was determined in 109 pooled samples of urine obtained from 14 preterm infants during the transitional period of fluid balance. It was shown by linear regression analysis that urine sodium concentration (mmol l -1 ) = 0.78 ×urine conductance -1.25. Urine sodium concentrations derived from the above formula were concordant with urine sodium measured directly when used to calculate daily sodium balance in all 14 infants.

Conclusion: Urine conductance can be accurately measured at the cotside by neonatal nurses and used to identify the timing of the postnatal transition from negative to positive sodium balance in preterm infants. These findings can help in making decisions on the introduction of postnatal sodium administration to preterm infants.     

Clinical measures to preserve cerebral integrity in preterm infants

Impaired psychomotor development, often anteceded by major intraventricular hemorrhage or periventricular leukomalacia, constitutes the most important long-term morbidity of very preterm infants. We reviewed randomized controlled trials aimed at reducing the incidence of brain damage, as detected by ultrasound, or neurodevelopmental impairment during follow-up of preterm infants. Preliminary reports of reduced rates of intraventricular hemorrhage obtained with administration of fresh frozen plasma, ethamsylate, phenobarbitone, or morphine have not been confirmed in subsequent larger trials. Early administration of indomethacin may reduce intraventricular hemorrhage without affecting long-term outcome. Pancuronium, inositol, and vitamin E decreased intraventricular hemorrhage rates but later psychomotor development was not examined. Thyroxin supplementation failed to improve neurodevelopmental outcome while protein enrichment of formula and individualized developmental care appear to be beneficial. The largest reductions in cerebral palsy and neurodevelopmental impairment were achieved by avoidance of postnatal steroids. This finding emphasizes the need to include these late endpoints in any randomized trial involving preterm infants.     

Early amplitude-integrated EEG correlates with cord TNF-α and brain injury in very preterm infants

Aim: To investigate if the early electroencephalogram (EEG) and amplitude-integrated EEG (aEEG) in very preterm infants is affected by perinatal inflammation and brain injury, and correlates with long-term outcome.
Methods: Sixteen infants born at 24–28 gestational weeks (median 25.5) had continuous EEG/aEEG during the first 72 h of life. Minimum and maximum EEG interburst intervals (IBI), and aEEG amplitudes were semi-automatically quantified and averaged over the recording period. Neonatal brain injury was diagnosed with repeated cranial ultrasound investigations. Nine cytokines from four time-points were analyzed during the first 72 h (umbilical cord blood, 6, 24 and 72 h), and outcome was assessed at 2 years of corrected age.
Results: Infants with neonatal brain injury (n = 9) had prolonged IBI, 11.8 (9.6–23.2) sec versus 8.2 (7.1–11.6) sec in infants (n = 7) without brain damage (p = 0.005). Handicap at 2 years (n = 8, including two infants without neonatally diagnosed brain injury) was associated with prolonged neonatal IBI and lower aEEG amplitudes. Also aEEG amplitudes were decreased in infants with neonatal brain injury. There was a significant positive correlation between the averaged IBI and cord blood TNF-α (rs = 0.595, p = 0.025).
Conclusion: Early EEG depression is associated with increased cord blood TNF-α, neonatal brain damage and handicap at 2 years.     

Cerebrospinal fluid drainage in posthaemorrhagic ventricular dilatation leads to improvement in amplitude-integrated electroencephalographic activity

Aim: Progressive posthaemorrhagic ventricular dilatation (PHVD) may induce abnormal amplitude-integrated electroencephalographic (aEEG) activity prior to clinical deterioration or significant cerebral ultrasound changes. These abnormalities might be ameliorated with cerebrospinal fluid (CSF) drainage. The aims of this study were to investigate the occurrence of aEEG-abnormalities with progressive PHVD in relation to clinical and cerebral ultrasound changes and to evaluate whether CSF drainage results in aEEG improvement.
Methods: aEEG and cerebral ultrasound scans were performed in 12 infants with PHVD, before and after CSF drainage, until normalization of aEEG occurred.
Results: aEEG was abnormal with progressive PHVD in all patients. Concurrently, 60% of the patients were clinically stable without deterioration in ultrasonographic cerebral abnormalities. Post drainage, continuous pattern was restored in all but one patient, whereas the frequency of discontinuous pattern decreased in nine patients and burst-suppression pattern decreased in all but one patient. Low-voltage pattern was only observed in one patient who suffered severe grade IV IVH and died one week after EVD placement. Sleep-wake cycling matured in 75%.
Conclusion: These findings demonstrate the impact of CSF drainage on compromised aEEG-activity associated with PHVD. aEEG changes indicative of impaired cerebral function were apparent before clinical deterioration or major ultrasound changes. These changes were reversible with CSF drainage. aEEG should therefore be used in addition to clinical observation and ultrasound when monitoring PHVD.     

High plasma cytokine levels, white matter injury and neurodevelopment of high risk preterm infants: assessment at two years

Background

Controversy exists regarding association of high levels of proinflammatory cytokines, neonatal morbidities and poor neurodevelopment outcome in very low birth weight infants.

Objective

To determine association between severity of early inflammatory response and neurodevelopment outcome in high risk very low birth weight infants.

Methods

Sixty-two very preterm infants with high risk for early-onset sepsis were followed up to 24 months corrected age. Blood sample was collected for IL-6, IL-8, IL-10, IL-1β, and TNF-α analysis. Neurodevelopment outcome by Bayley Scales of Infant Development II was assessed at 22 to 24 months. Magnetic Resonance Image was performed at least once during the first 12 months.

Results

In 24 (38.7%) MDI was < 85, and 16 (25.8%) had PDI < 85. Low birth weight was significantly associated with low MDI, and birth weight and periventricular leukomalacia were significantly associated with low PDI by multiple regression analysis. After controlling for birth weight and gestational age, none of the studied variables was associated with low MDI, and only periventricular leukomalacia with low PDI. Each additional 100 g in the birth weight reduced the probability of low MDI and PDI scores in 14%.

Conclusions

There was no association of high cytokines plasma levels with poor neurodevelopment outcome at 22 to 24 months' corrected age, suggesting that elevations of plasma proinflammatory cytokines early in life do not play an important role in pathophysiology of brain injury in high risk preterm infants.     

CSF cytokine levels in preterm infants may reflect systemic inflammation and are independent of gestation

Background

Among preterm infants, high concentrations of inflammatory mediators in cerebrospinal fluid (CSF) are associated with poor outcome. Previous studies have not indicated whether CSF concentrations of inflammatory mediators are associated with important confounders such as gestational age.

Aims

To examine associations between CSF concentrations of inflammatory mediators and gestational age, maternal features suggestive of inflammation, characteristics of the CSF sample or the presence of a systemic inflammatory response.

Study design and subjects

Aliquots of CSF obtained during routine investigation of potential sepsis among infants born before 35 weeks gestation were assayed for 17 mediators of inflammation using a fluorescent multi-bead analyser. Other information was collected from routine clinical records.

Results

39 infants were assessed. CSF levels of mediators of inflammation were not correlated with gestational age. CSF red blood cell counts were correlated with CSF concentrations of IL-6, GM-CSF and IL-17 (each p < 0.003). CSF lactate was correlated with CSF concentrations of IL-1β, IL-6, GM-CSF, G-CSF, IFN-γ and MIP-1β. CSF concentrations of IL-1β, IL-6, G-CSF, TNF-α and IFN-γ were higher in infants with a raised CRP within 24 h of delivery (each p < 0.003).

Conclusions

CSF concentrations of inflammatory mediators most probably reflect inflammatory pathologies and are not influenced by gestational age. They may also, however, reflect contamination with blood or systemic inflammation. CSF concentrations of inflammatory mediators may not provide a specific indicator of CNS inflammation.     

Visual performance in preterm infants with brain injuries compared with low-risk preterm infants

Background

Neonatal brain injuries are the main cause of visual deficit produced by damage to posterior visual pathways. While there are several studies of visual function in low-risk preterm infants or older children with brain injuries, research in children of early age is lacking.

Aim

To assess several aspects of visual function in preterm infants with brain injuries and to compare them with another group of low-risk preterm infants of the same age.

Study design and subjects

Forty-eight preterm infants with brain injuries and 56 low-risk preterm infants.

Outcome measures

The ML Leonhardt Battery of Optotypes was used to assess visual functions. This test was previously validated at a post-menstrual age of 40 weeks in newborns and at 30-plus weeks in preterm infants.

Results

The group of preterm infants with brain lesions showed a delayed pattern of visual functions in alertness, fixation, visual attention and tracking behavior compared to infants in the healthy preterm group. The differences between both groups, in the visual behaviors analyzed were around 30%. These visual functions could be identified from the first weeks of life.

Conclusion

Our results confirm the importance of using a straightforward screening test with preterm infants in order to assess altered visual function, especially in infants with brain injuries. The findings also highlight the need to provide visual stimulation very early on in life.