Pain and neurodevelopmental outcomes of infants born very preterm.

AIM: To investigate the impact of the level of pain experienced by infants born preterm on neurodevelopmental outcomes during their stay in a neonatal intensive care unit. METHOD: In this retrospective data analysis we included all surviving infants born preterm with a gestational age between 23 and 32 weeks from 2011 to 2015, who were assessed using the Neonatal Pain, Agitation, and Sedation Scale and examined at 1 year of age using the Bayley Scales of Infant Development. We excluded all infants who had suffered severe neurological morbidities and undergone surgical interventions. RESULTS: A total of 196 infants born preterm were included in the analyses: 105 in the 'no pain group' and 91 in the 'pain group'. Significant differences between the groups were detected for both mental and motor development (p = 0.003, 95% confidence interval [CI] 2.23-10.92; p = 0.025, 95% CI 0.64-9.78). The results remained significant after controlling for other important medical conditions (p = 0.001, 95% CI -19.65 to -5.40; p = 0.010, 95% CI -16.18 to -2.29). INTERPRETATION: Neonatal pain exposure was associated with altered neurodevelopmental outcomes of infants born very preterm at a corrected age of 12 months. This observation highlights the importance of adequate pain management to reduce the risk of poor neurodevelopmental outcomes in these vulnerable patients.

The power of N-PASS, aEEG, and BIS in detecting different levels of sedation in neonates: A preliminary study.

BACKGROUND: Sedatives are essential drugs in every intensive care unit in order to ensure the patient's optimal level of comfort. Avoiding conditions of over- and under-sedation is a challenge in a neonatal intensive care setting. Drug administration could be optimized by the concomitant use of objective methods to assess the level of sedation. AIMS: We aimed to look at the ability of different methods (Neonatal Pain, Agitation and Sedation Scale, amplitude-integrated Electroencephalogram, and Bispectral Index), and their combination, in detecting different level of sedation. METHODS: Twenty-seven neonates among whom 17 were receiving sedatives with or without opiate analgesics were monitored using the Neonatal Pain, Agitation and Sedation Scale, the amplitude-integrated Electroencephalogram, and the Bispectral Index. According to the expert opinion of two trained neonatologists, patients were categorized into three groups: no, light, and deep sedation. Four hours of simultaneous assessment of the Neonatal Pain, Agitation and Sedation Scale scores, Burdjalov scores (to summarize the amplitude-integrated Electroencephalogram trace), and Bispectral Index values were considered for the comparative analysis across these groups. RESULTS: All three methods could differentiate patients who were not sedated from those who were deeply sedated: median score 12 and 9, respectively, (95% CI of difference = 1.99-5.99, P = 0.001) for the amplitude-integrated Electroencephalogram Burdjalov score; median 1 and -5, respectively, (95% CI of difference = 2.99-8.00, P = 0.001) for the Neonatal Pain, Agitation and Sedation Scale; and median 48 and 37, respectively, (CI of difference = 1.77-22.00, P = 0.043) for the Bispectral Index. However none of them, used alone, was able to differentiate light and deep sedation: median score 10 and 9, respectively, for the amplitude-integrated Electroencephalogram Burdjalov score; median -2 and -5, respectively, for the Neonatal Pain, Agitation and Sedation Scale; and median 48 and 37, respectively, for the Bispectral Index. Only the amplitude-integrated Electroencephalogram and the Neonatal Pain, Agitation and Sedation Scale were able to differentiate between the conditions of no sedation and light sedation. Also, according to the area under the curves values, the combination of the Neonatal Pain, Agitation and Sedation Scale with the Burdjalov score derived from the amplitude-integrated Electroencephalogram showed the best accuracy in differentiating light and deep sedation. CONCLUSION: While none of the three methods alone was able to precisely differentiate between different levels of sedation, we suggest that using a combination of amplitude-integrated Electroencephalogram and Neonatal Pain, Agitation and Sedation Scale can be useful to distinguish between light and deep sedation in neonatal patients.

Amplitude-integrated electroencephalography shows that doxapram influences the brain activity of preterm infants.

AIM: The aim of this study was to measure the brain activity of preterm infants treated with caffeine citrate and doxapram for preterm apnoea, using amplitude-integrated electroencephalography (aEEG), to identify any adverse effects on cerebral function. METHODS: We analysed the aEEG tracings of 13 preterm infants <30 weeks of gestation before, during and after doxapram treatment, with regard to background activity (percentages of continuous and discontinuous patterns), occurrence of sleep-wake cycling and appearance of electrographic seizure activity. They were also compared with 61 controls without doxapram treatment. RESULTS: During doxapram treatment, aEEG tracings showed an increase in continuous background activity (19 ± 30% before treatment, 38 ± 35% during treatment) and a decrease in discontinuous patterns. In addition, they showed more frequent electrographic seizure activity (0% before treatment, 15 ± 37% during treatment) and less frequent sleep-wake cycling (92 ± 27% before treatment, 85 ± 37% during treatment) could be observed. These results were confirmed when compared to the control group. CONCLUSION: Doxapram treatment influences aEEG in preterm infants, showing higher percentages of continuous activity as well as more electrographic seizure activity and less sleep-wake cycling. It should, therefore, be used with caution in very preterm infants.

Amplitude-integrated electroencephalography in male newborns <30 weeks' of gestation and unfavourable neurodevelopmental outcome at three years is less mature when compared to females.

AIM: To investigate gender-related differences in amplitude-integrated electroencephalography (aEEG) associated with neurodevelopmental outcome at 3 years. METHODS: Preterms born <30 weeks' gestational age between 2000 and 2002 were prospectively included. aEEGs obtained within the first 2 weeks of life were classified according to aEEG composite scores - including background pattern, sleep-wake cycling (SWC) and seizure activity. Neurodevelopmental outcome was assessed at 3 years of age. RESULTS: Neurodevelopmental outcome data was available for 148 of 264 eligible infants - 64 showed a normal outcome and 84 an impaired outcome. A logistic regression model revealed a significant independent influence of IVH, analgetic/sedative/anticonvulsant medication, gestational age and gender on aEEG composite scores. Odds ratios for having an abnormal aEEG composite score within the first 2 weeks of life for 'female sex', 'no IVH', 'no medication' and 'gestational age' were calculated. aEEG did not differ between males and females with normal outcomes. In patients with abnormal outcome, however, male preterms showed more burst-suppression patterns and less SWC when compared with female preterms. CONCLUSION: Being male with an abnormal outcome at 3 years of age is reflected by a less mature early aEEG when compared with the one of females. This association is independent of IVH and medication and was less evident with increasing gestational age.

Impact of Retinopathy of Prematurity on Visual Motor Integration.

BACKGROUND: Preterm infants are at risk for neurodevelopmental deficits. An association between retinopathy of prematurity (ROP) and impaired cognitive outcome has already been described. However, less is known about the impact of ROP on visual motor integration (VMI), which is a prerequisite not only for fine motor abilities but also for further school skills. Therefore, the aim of this study was to retrospectively investigate the impact of ROP on VMI at preschool age. METHODS: The study was conducted at the Medical University of Vienna, including patients born between January 2009 and December 2014 with a gestational age of less than 30 weeks and/or a birth weight of less than 1,500 g. VMI was determined by Beery-Buktenica Developmental Test of Visual Motor Integration (Beery VMI) at the age of 5 years. RESULTS: Out of 1,365 patients, 353 met inclusion criteria for this study. Two hundred sixteen of them had no ROP, while 137 had ROP (stage 1: n = 23, stage 2: n = 74, stage 3: n = 40). Mean value of the Beery VMI score was significantly lower in the ROP group compared to the No-ROP group (90 ± 16 vs. 99 ± 14; p < 0.01). By correcting for other important medical conditions, ROP still had a significant impact on Beery VMI score (p < 0.01). Particularly, lower scores were found for stage 2 (p < 0.01) and stage 3 (p < 0.01). CONCLUSION: Beery VMI scores were significantly lower in preterm infants with ROP stage 2 and 3 than in infants without ROP. This study shows the negative impact of ROP on VMI skills at preschool age, even after adjustment for key demographic and medical characteristics.

Influence of site differences between urban and rural American and Central European opioid-dependent pregnant women and neonatal outcome characteristics.

BACKGROUND: Multi-center trials enable the recruitment of larger study samples, although results might be influenced by site-specific factors. METHODS: Site differences of a multi-center prospective double-blind, double-dummy randomized controlled trial (7 centers: Central Europe (Vienna)/USA (3 urban/3 rural centers)) comparing safety and efficacy of methadone and buprenorphine in pregnant opioid-dependent women and their neonates. RESULTS: Urban US women had the highest rate of concomitant opioid (p = 0.050) and cocaine consumption (p = 0.003), the highest dropout rate (p = 0.001), and received the lowest voucher sums (p = 0.001). Viennese neonates had significantly higher Apgar scores 1 min (p = 0.001) and 5 min after birth (p < 0.001) and were more often born by cesarean section (p = 0.024). Rural US newborns had a significantly shorter neonatal abstinence syndrome treatment duration compared to Viennese and urban US sites (p = 0.006), in addition to other site-specific differences, suggesting a more severely affected group of women in the urban US sites. CONCLUSION: This clinical trial represents a role model for pharmacological treatment in this unique sample of pregnant women and demonstrates the clinical importance of considering site-specific factors in research and clinical practice.

Amplitude-integrated EEG pattern predicts further outcome in preterm infants.

Changes in EEG background activity are powerful but nonspecific markers of brain dysfunction. Early EEG and amplitude-integrated EEG (aEEG) pattern predict further neurodevelopmental outcome in term infants; however, sufficient data for prognostic value of aEEG in preterm infants are not available so far. The aim of the study was to evaluate whether aEEG predicts further outcome and to compare it to cerebral ultrasound assessment. In 143 preterm infants, aEEG within the first 2 wk of life and outcome data at 3 y of age (Bayley Scales) could be obtained.aEEG was classified into a graded score according to background activity, appearance of sleep-wake cycling, and occurrence of seizure activity. In preterm infants, aEEG was significantly associated with further outcome. Specificity was 73% for assessment within the first and increased to 95% in the second week of life, whereas sensitivity stayed nearly the same 87% (first week) to 83% (second week). Cerebral ultrasound showed a specificity of 86% within the first and second week, sensitivity also stayed nearly the same (74 and 75%). aEEG has a predictive value for later outcome in preterm infants and can be used as an early prognostic tool.

The influence of music on aEEG activity in neurologically healthy newborns ≥32 weeks' gestational age.

AIM: Music is increasingly being used in neonatal intensive care units to aid neurodevelopmental care. The aim of this pilot study was to examine the possible effects of music on quiet sleep (QS) in neurologically healthy newborns. METHODS: Twenty newborns ≥32 weeks' gestational age admitted to the neonatal intensive care unit at The Royal Children's Hospital in Melbourne for specialist consultation were randomly assigned to experimental or control groups. Ten subjects were exposed to music (Music for Dreaming, (Sound Impressions, Pty. Ltd.) using a CD player (50-55 decibel A). Amplitude-integrated EEG was recorded on the BrainZ Monitor (BRM2, Version 8.0, Natus). Background pattern, presence and quality of sleep-wake cycles (SWC) were assessed before and after exposure to music. RESULTS: All 20 subjects showed continuous background patterns with developing SWC. Whereas no subject in the control group showed differences in their QS and eight patients in the intervention group showed lower minimum amplitudes of their QS after music exposure. Also, the length of QS and interval between QS epochs became progressively longer in all ten subjects of the intervention group. CONCLUSION: We report a trend to more mature SWC in subjects who were exposed to music when compared to controls suggesting that there might be a small effect of music on quiet sleep in newborns.

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.

Caffeine monitoring in infants: comparison of automated (VITROS 5, 1 FS) chemistry system versus HPLC analysis.

This is the first study comparing the caffeine testing by HPLC to the MicroTip Technology patented by Ortho-Clinical Diagnostics. For the determination of the precision for intra-run and day to day variances, control materials with concentration ranges between 2.3 microg/mL and 23.3 microg/mL were used. Test evaluation was done using plasma samples. The coefficient of variation for intra-run precision was calculated to range from 4.3% to 2.1%. The coefficients of variation for the day-to-day precision were between 4.9% and 2.3%. A coefficient of correlation of 0.99% was calculated for the comparison of the two methods. In the statistical analysis of the comparison of the methods. Differences between + 4.5% and - 0.92% could be found. The HPLC system must be ready for use at any time necessitating maintenance and increased costs. This, in addition to the low sample throughput for caffeine analysis and the findings of this study favour the use of an automated clinical chemistry system.

Renal failure, comorbidity and mortality in preterm infants.

OBJECTIVE: To evaluate patient characteristics and risk factors for mortality in critically ill preterm infants with renal failure, with a special focus on infants with extremely low birth weight. DESIGN: Retrospective cohort study with five year follow-up of all premature infants who were treated in the neonatal intensive care unit in 2002 and developed postnatal serum creatinine > or =1.5 mg/dl and/or urine output <1 ml/kg per h. SETTING: Tertiary Care University Hospital of the Medical University of Vienna PATIENTS: Sixteen of 359 premature infants (9 boys, 7 girls) fulfilled the inclusion criteria for renal failure. Their median gestational age was 30 weeks (range 24-36) with a median birth weight of 811.5 g (range 588-2662). MEASUREMENTS AND MAIN RESULTS: The most common causes of renal failure were sepsis and ischemic events. All infants were managed conservatively with corrections of fluids, electrolytes and acidosis, including medication with diuretics and dopamine. Eleven infants with renal failure (69%) died in multiorgan failure. Infants with low urine output, higher scores for failed organs or low birth weight were significantly more likely to die. Infants with very low birth weights had higher scores for failed organs (all P < 0.05). CONCLUSION: Oliguria/anuria, multiorgan failure and immaturity were significant risk factors for mortality in preterm infants with renal failure. Further studies and/or more registry data are needed to determine whether these infants died with or from renal failure, and whether dialysis would improve outcome in this special population.

Amnionitis with Ureaplasma urealyticum or other microbes leads to increased morbidity and prolonged hospitalization in very low birth weight infants.

OBJECTIVE: To investigate the influence of culture proven intrauterine infection on preterm morbidity and to test the effect of antimicrobial treatment. METHODS: Retrospective cohort study conducted between October 1997 and February 2001 in patients with preterm premature rupture of membranes or preterm labor. Vaginal swabs were sampled and amniocentesis for microbiologic culture of the amniotic fluid was performed. Patients with Ureaplasma urealyticum in the amniotic fluid were treated with josamycin. Infants were followed post partum according to birth weight, gestational age, APGAR score and infant morbidity. RESULTS: In 49 eligible patients, 40% of cultures were positive, 22% for Ureaplasma urealyticum, 12% for other bacteria and 6% for candida. Children of mothers with positive amniotic fluid cultures had significantly lower gestational ages (26+4 weeks for Ureaplasma urealyticum [p=0.04] and 25+5 weeks for other microorganisms [p=0.0017] versus 28+6 weeks for mothers with negative amniotic fluid cultures) and lower birth weights (975 g [n.s.] and 828 g [p=0.0072] versus 1,041 g) but were appropriate for their gestational ages. 33.3% and 66.7% versus 24% of the children were mechanically ventilated [n.s.], duration of mechanical ventilation was 5.3 [p=0.02] and 10.1 days [p=0.04] versus 1.4 days, and prevalence of chronic lung disease was 38% and 33% versus 11% [n.s.]. Prevalence of severe intraventricular hemorrhage (12.5% [n.s.] and 33% [p=0.04] versus 3.4%) and nosocomial infections (50% for both groups of positive cultures versus 10.3% for negative cultures, p=0.02 and 0.03, respectively) was higher and median length of stay was significantly longer (121 [p=0.02] and 107 days [p=0.03] versus 60 days) in these patients. Maternal positive vaginal swab cultures were not associated with any of the above-mentioned factors. In none of the patients treated with macrolids for proven Ureaplasma urealyticum amnionitis could the microbes be eradicated. CONCLUSION: Maternal positive amniotic fluid cultures have been associated with lower gestational age and lower birth weight. Rate of infant morbidity was higher and length of stay was significantly longer in this group. Positive vaginal swabs were not predictive for infant morbidity. Treatment of mothers showing positive amniotic fluid cultures with macrolids was not effective.

Dead-space washout by split-flow ventilation. A new method to reduce ventilation needs in premature infants.

OBJECTIVE: Chronic lung disease caused by volutrauma is one of the most important consequences of preterm delivery. In this pilot study a new method is presented that consists of flushing part of the dead space with fresh gas in order to reduce high tidal volumes, the chief cause of volutrauma. The aim of the study was to evaluate if the new method could reduce ventilatory effort in preterm infants by diminishing dead space. DESIGN AND SETTING: In split-flow ventilation, gas required for dead-space washout is split off from the regular ventilation circuit. The split flow bypasses the apparatus dead space and fills it retrogradely with fresh breathing gas, mainly in the pause between exhalation and inspiration. The mean per-minute ventilation and ventilation index after 12 h of conventional ventilation were compared with corresponding mean values after 12 h of split-flow ventilation in 17 preterm infants weighing <2,000 g. Statistical analysis was performed using the T -test for matched pairs. RESULTS: After switching from conventional ventilation to split-flow ventilation, the mean per-minute ventilation per kilogram of body weight decreased significantly from a mean value of 0.314+/-0.097 l/kg/min to 0.190+/-0.043 l/kg/min ( p <0.001), while the ventilation index decreased significantly from 28.47+/-7.48 to 16.10+/-4.13 ( p <0.001). CONCLUSION: Split-flow ventilation significantly reduces apparatus dead space during ventilation in preterm infants. This leads to reduced ventilatory effort.

Mortality and morbidity in extremely preterm infants (22 to 26 weeks of gestation): Austria 1999-2001.

OBJECTIVE: The aim of this retrospective study was to analyze the mortality and morbidity for extremely preterm infants with a gestational age from 22 to 26 weeks. All infants were born in Austria during the years 1999-2001. METHODS: Data were collected from 16 neonatal intensive care units in Austria. Main outcome criteria were mortality, the rates of chronic lung disease (CLD) and severe retinopathy of prematurity (ROP, stage > or =3) to determine the short-term outcome; the rate of cerebral palsy (CP) at the corrected age of twelve months to assess the long-term outcome. RESULTS: Overall, 796 preterm infants with a gestational age less than 27 weeks were born in Austria and 581 (73%) were registered as live-born infants. Of those live born, 508 (87%) were analyzed. The mortality rates were 83%, 76%, 43%, 26% and 13% for 22, 23, 24, 25 and 26 weeks' gestation, respectively. The rates of CLD were 33% (22 weeks), 36% (23 weeks), 42% (24 weeks), 31% (25 weeks) and 22% (26 weeks). The rates of ROP of stage > or =3 were 0% (22 weeks), 29% (23 weeks), 23% (24 weeks), 18% (25 weeks) and 10% (26 weeks). The rates of CP at the corrected age of 12 months were 33%, 50%, 33%, 26% and 25% for 22, 23, 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: The results of this national study are in accordance with the international literature: mortality and morbidity increased with decreasing gestational age.

Being Born Small for Gestational Age Influences Amplitude-Integrated Electroencephalography and Later Outcome in Preterm Infants.

BACKGROUND: The impact of growth restriction on perinatal morbidity is well known, but electroencephalographic (EEG) data on its influence are still scarce. OBJECTIVES: We aimed to analyze the influence of being born small for gestational age (SGA; defined as a birth weight <10th percentile) on the amplitude-integrated EEG (aEEG) score in the first 2 weeks of life in preterm infants born before 30 weeks of gestation, and its impact on later outcome. METHODS: aEEG data obtained within the first 2 weeks of life on preterm infants born SGA and before 30 weeks of gestational age (GA) were analyzed retrospectively using a combined score [including background activity, occurrence of sleep-wake cycles (SWC) and suspected seizure activity]. Neurodevelopmental outcome was evaluated at 24 months by means of the Bayley Scales of Infant Development II and a standardized neurological examination. RESULTS: One hundred and thirty-six patients were included (47 SGA and 89 controls). Infants with SGA had abnormal aEEG scores significantly more often (57 vs. 24%, p = 0.002) than infants born appropriate for gestational age (AGA). They also displayed SWC less frequently (65 vs. 96%, p = 0.001), were more likely to develop seizure activity (15 vs. 4%, p = 0.013) and had a normal neurodevelopmental outcome at the age of 2 years less frequently (36.2 vs. 59.6%, p = 0.02). CONCLUSION: Preterm infants born SGA and before 30 weeks of GA had less optimal scores on early aEEG and a poorer neurodevelopmental outcome at 24 months than the AGA controls.

Spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis.

BACKGROUND: Idiopathic spontaneous intestinal perforation (SIP), a distinct clinical entity different from necrotizing enterocolitis (NEC), has an increasing prevalence in very-low-birth-weight infants. The aims of our study were to define patient characteristics and potential risk factors for premature infants with SIP compared with infants subjected to surgical treatment for NEC. STUDY DESIGN: The medical records of 29 premature infants with either SIP (n = 13) or NEC (n = 16) were reviewed retrospectively. RESULTS: Infants who experienced SIP were smaller at birth, had lower Apgar scores, and required more intensive neonatal resuscitation. An increased rate of premature rupture of membranes in infants with SIP (8/13 versus 6/16) was not associated with a higher rate of infection in mothers or infants. The onset of illness in SIP was significantly earlier than in NEC (p = 0.022). In contrast to patients with NEC (7/16), 11 of 13 patients in the SIP group had received indomethacin (p = 0.02). Bluish discoloration of the abdomen (8/13), a gasless abdomen (8/13), and the absence of pneumatosis intestinalis (0/13) were further significant markers in infants with SIP. At operation, SIP was always located in the terminal ileum in an antimesenteric position (13/13), and the remaining bowel appeared grossly normal. In most cases of SIP (10/13), the histologic investigation revealed an area of hemorrhagic necrosis without the typical coagulation necrosis seen predominantly in NEC. CONCLUSIONS: Based on clinical presentation and radiologic and intraoperative findings, SIP is a distinct pathologic entity in very-low-birth-weight infants and can be differentiated from classic NEC. Detected early, SIP can be treated by simple procedures (sutures, or resection and primary anastomosis) with a low rate of morbidity and mortality.

Interleukin-8 predicts 60-day mortality in premature infants with necrotizing enterocolitis.

OBJECTIVE: The purpose of this study was to evaluate the predictiveness of circulating interleukin (IL)-8 for 60-day mortality in premature infants with necrotizing enterocolitis (NEC). BACKGROUND: NEC affects up to 5% of premature infants and remains a leading cause of mortality among neonates. METHODS: A total of 113 infants with surgically (n=50) or medically (n=63) treated NEC were retrospectively analyzed. Laboratory parameters including serum IL-8 were assessed at the diagnosis of NEC and during the preoperative workup. RESULTS: The 60-day mortality was 19% (22/113), 10% (6/63) in medical and 33% (16/50) in surgical NEC. IL-8 levels significantly correlated with 60-day mortality (odds ratio: 1.38; CI 1.14-1.67; p=0.001). Median IL-8 levels at diagnosis were significantly higher in neonates who were later treated surgically (median=2625 pg/ml; range: 27-7500) compared with those treated medically (median=156 pg/ml; range: 5-7500; p<0.001). The AUC to discriminate between medical and surgical NEC was 0.82 (CI, 0.74-0.90), and an exploratory IL-8 cutoff point could be established at 1783 pg/ml (sensitivity of 90.5%; specificity of 59.2%). CONCLUSIONS: Our findings that serum IL-8 (i) correlates directly with 60-day mortality and (ii) differs significantly between medically and surgically treated infants may change the process of therapeutic decision making in NEC.

Serum levels of interleukin-8 and gut-associated biomarkers in diagnosing necrotizing enterocolitis in preterm infants.

BACKGROUND: In recent years several potential biochemical markers have been evaluated to facilitate a reliable diagnosis of necrotizing enterocolitis (NEC), but none have made progress to clinical routine. We performed a comparative assessment in premature infants to evaluate the diagnostic value of the routinely available cytokine interleukin (IL)-8, and two promising experimental biomarkers, the gut barrier proteins liver fatty acid binding protein (L-FABP) and intestinal fatty acid binding protein (I-FABP), respectively, for the diagnosis of NEC. METHODS: IL-8, L-FABP, and I-FABP concentrations were analyzed in the serum of 15 infants with NEC and compared with 14 gestational age-matched infants serving as a control group. RESULTS: Serum concentrations of I-FABP, L-FABP and IL-8 were significantly higher in infants with NEC compared with controls. IL-8 showed the highest diagnostic value with an area under the curve of 0.99, followed by L-FABP and I-FABP. In addition we found a significant correlation between IL-8 and both FABPs in infants with NEC. CONCLUSION: Our results further advocate the possible role of IL-8 as a specific marker for NEC. The diagnostic value of IL-8 seems to be superior to I-FABP, and similar to L-FABP. The routinely availability facilitates IL-8 as a possible candidate for further clinical investigations.

Can neurophysiological assessment improve timing of intervention in posthaemorrhagic ventricular dilatation?

OBJECTIVE: Intraventricular haemorrhage is still the most common cause of brain lesion in preterm infants and development of a posthaemorrhagic ventricular dilatation (PHVD) can lead to additional neurological sequelae. Flash visual evoked potentials (fVEP) and amplitude-integrated electroencephalography (aEEG) are non-invasive neurophysiological monitoring tools. The aim of the study was to evaluate fVEPs and aEEGs in preterm infants with progressive PHVD prior to and after neurosurgical intervention for cerebrospinal fluid removal and to correlate the findings with severity of ventricular dilatation. DESIGN: fVEPs and aEEGs were performed weekly in infants with developing PHVD. As soon as the ventricular index reached the 97th percentile recordings were performed twice a week. METHODS: 17 patients admitted to the neonatal intensive care unit of the Medical University of Vienna who developed progressive PHVD were evaluated using fVEP and aEEG until and after reduction of intracranial pressure by placement of an external ventricular drainage. RESULTS: In all 17 cases (100%) wave latencies of fVEP increased above normal range and aEEG showed increased suppression in 13 patients (76%) with increasing ventricular dilatation. Both methods showed normalisation of patterns mostly within a week of successful therapeutic intervention (mean 8.5 days). Both changes in fVEP latencies and aEEG background patterns were detected before clinical signs of elevated intracranial pressure occurred. In only 10 patients (58.8%) ventricular width exceeded the 97th percentile+4 mm. CONCLUSIONS: fVEP and aEEG are useful additional tools for the evaluation of preterm infants with progressive PHVD.

Comprehensive evaluation of 11 cytokines in premature infants with surgical necrotizing enterocolitis.

OBJECTIVE: A prospective study to investigate the pattern of pro- and anti-inflammatory cytokine responses in neonates with surgical necrotizing enterocolitis (NEC) and identify those cytokines being the most promising for future research. METHODS: A panel of 11 different cytokines were measured in 9 infants with proven NEC and compared with 18 age-matched healthy neonates. RESULTS: The serum concentrations of the interleukins (IL)-6, IL-8, and IL-10 were significantly (32-fold to 56-fold) higher in NEC infants compared with controls. In contrast, IL-5, IFN gamma, IL-4 and IL-2 showed slightly (1.4-fold to 5.9-fold) lower levels in the NEC samples. However, these cytokines showed a very low absolute concentration in infants with NEC and in controls. The sum of the serum concentrations of IL-6, IL-8 and IL-10 was able to clearly separate infants with NEC from control samples. IL-1 beta and TNF-alpha showed no statistically different levels. The serum levels of TNF-beta and IL-12p70 were below the detection limit in more than 50% of all samples per group. CONCLUSION: In spite of strong local inflammation only three out of eleven cytokines (IL-6, IL-8, and IL-10) showed strongly increased serum levels indicating an important role of them in the pathogenesis of NEC. At least two of these three cytokines were elevated in every single NEC patient. Thus, longitudinal monitoring of combined IL-8, IL-6, and IL-10 levels could reveal their potency in being clinical relevant markers in NEC.