Early end-tidal carbon monoxide levels and neurodevelopmental coutcome at 3 years 6 months…
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Published in final edited form as:
Dev Med Child Neural. 2011 December ; 53(12): 1113-1118. doi:10.1111/j.1469-8749.2011.04110.x.
Early end-tidal carbon monoxide levels and neurodevelopmental coutcome at 3 years 6 months of age in preterm infants
Cornelie A Blok1, Tannette G Krediet1, An nemiek Kavelaars2, Cori ne koopmanEsseboom1, Hend rik J Vreman3, and Frank Van Bel1
1Department of Neonatology, University Medical Center Utrecht, the Netherlands 2Laboratory of Neurolmmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, the Netherlands 3Neonatal and Developmental Medicine Laboratory, Stanford University School of Medicine, Stanford, CA, USA
Abstract
Aim-Increased end-tidal carbon monoxide (ETCOc) and cytokines in preterm infants are related to bronchopulmonary dysplasia and intraventricular haemorrhages. The aim was to study the predictive value of ETCOc and cytokine Levels for long-term outcome.
Methods-This study comprised 105 very preterm infants (57 males, 48 females; gestational age range 25wk 5d-3lwk 4d; birthweight 610-2100g) who were admitted to a neonatal intensive care unit between 1 February and 31 December 2002. ETCOc, plasma tumour necrosis factor alpha (TNF α) and interleukins (IL) 6 and 8, and malondialdehyde (MDA, a marker of lipid peroxidation), were measured at days 1, 3, and 5 of life and related to outcome at 3 years 6 months of age (Griffiths Mental Developmental Scales).
Results-Of the 105 infants, 69 were eligible for follow-up (37 male; 32 female; bronchopulmonary dysplasia, n=l2). ETCOc at 0 to 24 hours was higher in infants with adverse outcome (Griffiths developmental quotient <85, n=l 5) compared with favourable outcome (2.7 SD 0.7 vs 2.0 SD 0.5; p <0.05). MDA and cytokines did not differ between groups. Regression analysis with bootstrapping of independent variables (gestational age, birthweight, ETCOc, TNF-α,IL-6, IL-8, and bronchopulmonary dysplasia) showed that ETCOc was the only parameter that correlated with outcome. The sensitivity and negative predictive value of ETCOc for adverse outcome were 93% and 85% respectively.
lnterpretati n-Adverse neurodevelopment al outcome is associated with increased endogenous carbon monoxide. ETCOc less than 2.0ppm during the first day indicates a favourable outcome.
Carbon monoxide (CO) is a normal oxidative degradation product of haem, and diffuses from the blood to the lungs and alveolar air. CO production is increased during oxidative stress and inflammation, such as in chronic lung disease in adults. 1 Respiratory distress syndrome (RDS) in the very preterm infant has also been associated with inflammatory processes and oxidative stress.2 Buss et al.3 found lipid peroxidation products in tracheal aspirates from unwell preterm infants. Also, others have found inflammatory cytokines, such as interleukin 8 (IL-8) and IL-10, and oxidative products in bronchoalveolar lavage fluid.4,5 In these very preterm infants with severe infant RDS, the lipid peroxidative processes lead to an increase in CO in exhaled air.6,7 Increased levels of end-tidal CO (ETCOc) corrected for inhaled CO during the first days of life appeared to be predictive for the development of bronchopulmonary dysplasia (BPD) in preterm infants, as shown by our group and others.6,8
Several reports suggest a direct adverse effect of BPD on the immature brain, in particular cerebral white matter, and on neurodevelopmental outcome.9-11 Experimental and clinical studies indeed suggest that inflammatory processes play a role in the aetiology and pathogenesis of periventricular /intraventricular haemorrhages12,13 and white matter damage, leading to adverse neurodevelopmental outcome.14,15
Therefore, we studied the relationship between early ETCOc values and neurodevelopmental outcome at 3 years 6 months of age in a cohort of 105 very preterm infants, with a gestational age of less than 32 weeks. Since the working hypothesis was that inflammatory responses and peroxidative processes are important mediators of lung and brain damage, 1,6 we determined plasma proinflammatory cytokines and malondialdehyde (MDA) levels as an indicator of lipid peroxidation simultaneously with the ETCOc. We determined the relation of these parameters, obtained in the early neonatal period, with neurodevelopmental outcome at 3 years 6 months of age using Griffiths assessment scales.16
Methods
All preterm infants with a gestational age of less than 32 weeks consecutively admitted to the neonatal intensive care unit between 1 February and 31 December 2002 were included in the study after the receipt of informed parental consent. The study was approved by the Medical Ethics Committee of the University Medical Center, Utrecht, the Netherlands.
Obstetric and neonatal data were collected prospectively (see Table I). Endogenously produced CO, usually quantitated as ETCOc, was measured within the first 24 hours of age and on the third and fifth day of life using the CO-Stat End Tidal Breath Analyzer (Natus Medical Inc., San Carlos, CA, USA) by two investigators who were not involved in the follow-up part of the study.6,17 Briefly, this non-invasive bedside instrument uses electrochemical sensors for the measurement of CO and hydrogen and an infrared optical bench for the measurement of end-tidal carbon dioxide. Because excessive concentrations of hydrogen interfere with accurate CO measurements, the instrument will not permit them when breath hydrogen concentrations are greater than 50ppm or µl/l. Carbon dioxide measurements and breath-rate measurements can be used by the clinician to evaluate the quality of sampling. This instrument has a range of 0.0 to 25.0ppm CO with a resolution of 0.1ppm. Its accuracy is 0.3ppm or 10% of the reading (whichever is greater). A single-use flexible nasal sampler (1.Smm outside diameter) was connected to the CO-Stat Analyzer. It was inserted either approximately 6mm into the nostril when infants were breathing spontaneously and/or on continuous positive airway pressure or, in the case of mechanical ventilation, into the proximal part of the endotracheal tube via a T-connector. During 90 seconds of breathing or artificial ventilation, expired air was continuously sampled for determination of ETCOc and end-tidal carbon dioxide. On completion of the procedure, the sampler was disconnected from the device and the CO concentration in room air was determined and used to correct for CO in the inhaled air (typically 0.5ppm). In the case of mechanical ventilation , CO in room air was used as a substitute for correction of inhaled CO. If the infants were ventilated with high-frequency oscillation, the ventilator (Stephanie SW 301, F. Stephan Medicin Technik, Gackenbach, Germany) was switched to the conventional mode during the 90-second sampling time. Using the CO-Stat Analyzer, ETCOc could be measured reliably and reproducibly in these tiny ventilated infants.6,8 Measurements were performed in duplicate and the mean value of the two measurements was reported . ETCOc was expressed as ppm (µl/l). Measurements rejected by the CO-Stat Analyzer owing to excessive levels of hydrogen in the exhaled air were excluded.
Arterial blood pressure was monitored and blood was sampled via an indwelling arterial catheter. Simultaneously with the ETCOc measurements, blood was sampled for determination of total bilirubin, proinflammatory cytokines IL-6, IL-8, and TNF α,and MDA as an indicator of lipid peroxidation . Cytokine levels in plasma were then determined by enzyme-linked immunosorbent assay (Pelikine, CLB, Amsterdam, the Netherlands) .When cytokines were not detectable, the minimum detectable level was used in the calculations. Detection limits were 2.5pg/ml for IL-6 and IL-8 and 3.4pg/ml for TNF α and MDA in plasma was measured using a high-performance liquid chromatography method after mixing equal volumes of plasma and 10% (weight/volume) metaphosphoric acid containing 2mmol/l desferrioxamine mesilate and stored at -80℃.
The severity of RDS was assessed using clinical symptoms and radiographic signs and graded as none, moderate, or severe. Moderate RDS was classified as the radiographic classification I or II as defined by Giedion et al.,18 without the need for surfactant replacement therapy. Severe RDS was classified as Giedion grading Ⅲ or Ⅳ and/or the need of surfactant replacement therapy. Decisions on surfactant replacement therapy were made by the attending neonatologist, who was blinded to the study results, and were based on a defined protocol used in our unit: infants ventilated because of RDS within l hour after birth with a gestational age of less than 29 weeks and with gestational age greater or equal to 29 weeks with FiO2 greater than 0.3 and mean airway pressure greater than 10cmH2O received surfactant replacement therapy. BPD was considered if there was still extra oxygen dependency at 36 weeks of gestational age19 and characteristic radiographic signs were present.
Diagnosis and grading of periventricular intraventricular haemorrhages was performed as follows: infants were scanned with a mechanical scanner with a multifrequency transducer (5-7.5-l0MHz crystals). The frequency was 7.5MHz whenever possible to ensure the best possible resolution. Scans were always performed within 0 to 12 hours after birth, every 24 hours up to day 3, at day 7, and then weekly until discharge, or more frequently if necessary, by the attending neonatologist, who was unaware of the study results. Periventricular¬ intraventricular haemorrhage was graded as reported previously:20 grade I, small germinal layer haemorrhage ; grade Ila, germinal layer haemorrhage plus intraventricular haemorrhage, filling the lateral ventricle less than 50%; grade Ⅱb, large intraventricular haemorrhage distending the ventricle more than 50%; and grade Ⅲ,intraventricular haemorrhage associated with (unilateral) parenchymal involvement due to venous or haemorrhagic infarction.
Griffiths Mental Developmental Scales, which are routinely used at the outpatient clinic at the uncorrected age of 3 years 6 months of age, were used to assess motor and cognitive performance.16 ,21,22 The Griffiths scales comprise six subscales (personal and social, hearing and speech, locomotor, eye-hand co-ordination, performance, and practical reasoning domains), from which an overall developmental quotient is derived. A lower developmental quotient reflects a worse neurodevelopmental performance. A developmental quotient less than 85 (100-lSD) was considered as an adverse neurodevelopmental outcome, whereas children with a developmental quotient of 85 or more were considered to have a favourable neurodevelopmental outcome.
Statistical analysis
Data are summarized as means (1SD) or median and ranges where appropriate. Differences in clinical and laboratory data between groups (favourable vs adverse neurodevelopmental outcome) were assessed by the Mann-Whitney U test, and in case of nominal variables by the X2 test. Within-group differences in proinflammatory cytokines, MDA, and ETCOc between days 1, 2, and 3 were assessed with analysis of variance for repeated measures or Kruskal Wallis one-way analysis of variables, where appropriate, followed by the Scheffe’s procedure (analysis of variance)23 or Wilcoxon’s rank-sum test (Kruskal Wallis test) if a significant difference was found. Regression analysis was used to reveal whether neurodevelopmental outcome (dependent variable) was related to ETCOc, proinflammatory cytokines, or MDA at day 1, 3, or 5 and BPD (independent variables). Also, gestational age (wks) and birthweight (g) were included as independent variables in the analysis. This analysis was run with bootstrapped confidence intervals with all variables included (50 replications yielded).24 ,25 The temporal relationship among ETCOc, proinflammatory cytokines, and plasma MDA was investigated using simple linear regression analysis. For statistical analysis, Statview Ⅱ was used (Abacus Concepts, Berkeley, CA, USA). Finally, receiver operating characteristic curves were created for individual parameters using MedCalc software (MedCalc 5.00.019, Marienkerke, Belgium), and the area under the receiver operating characteristic curve was determined. Sensitivity, specificity, positive predictive value, and negative predictive value of the individual ETCOc concentrations to predict neurodevelopmental outcome were calculated using the cut-off values resulting from receiver operating characteristic analysis.26 Statistical significance was assumed for p<0.05.
Results
Ne natal characteristics and neurodevelopmental outcome at 3 years 6 months of age
Scores on the Griffiths Mental Developmental Scales were available for 69 out of the 105 infants initially included in the present study. Nine children died before the age of 3 years 6 months (almost all in the neonatal period) . The remaining 27 children were lost to follow-up because the family moved away from the Utrecht area or withdrew from follow-up owing to lack of motivation. This group was not significantly different in terms of gestational age, birthweight , ETCOc, MDA, or cytokine values from the 69 children included in the follow-up study. Fifty-four infants had a favourable neurodevelopmental outcome (median developmental quotient 97, range 85 127) and 15 infants had an adverse neurodevelopmental outcome (median developmental quotient 81, range 75-84). The lowest score was found in the speech subscale, with a median of 64 (range 56-79). Two children had mild cerebral palsy, one in the adverse outcome group and one in the favourable outcome group. Clinical characteristics of both groups during the neonatal period are shown in Table Ⅰ.No differences were found for gestational age, birthweight, Apgar score, or plasma total bilirubin values on day 1, 3, or 5, or incidence of severe RDS. Children were diagnosed as asphyxic at birth if the Apgar score was less than 5 at 5 minutes of age. This was the case for only two infants in the favourable outcome group. There were no infants with an Apgar score less than 5 at 5 minutes in the adverse outcome group. No seizures were detected in any of the included infants. However, treatment with antenatal glucocorticoids, incidence of periventricular -intraventricular haemorrhages larger than grade Ⅱ, incidence of no RDS or moderate RDS, and subsequent development of BPD in children with adverse neurodevelopmental outcome was significantly higher than in those infants with a favourable neurodevelopmental outcome. Moreover, adverse neurod evelopmental outcome was significantly more frequent in males: 12 out of 15 infants in the adverse outcome group were male compared with only 25 of the 59 infants in the favourable outcome group.
ETCOc, proinflammatory cytoki nes, and MDA
Table II shows the proinflammatory cytokines IL-6, IL-8, and TNF-α, and ETCOc and MDA values in both groups on days 1, 3, and 5 of age. No differences were detected for the cytokines and MDA, which actually showed wide ranges. ETCOc, however, was significantly higher on day 1 in the adverse neurodevelopmental outcome group than in the favourable outcome group (2.7 SD 0.7 vs 2.0 SD 0.5;p =0.007). During the following days, no differences in ETCOc between groups were detected. No differences at any point of postnatal age were found when we compared ETCOc, MDA, and cytokine values between males and females.
Figure 1 shows a simple regression plot between individual ETCOc measurements and the developmental quotient score, which showed a significant negative correlation (r2= 0.162;p=0.0011). As can also be seen in Figure 1, infants with ETCOc values lower than 2ppm all had a favourable outcome (Griffiths developmental quotient >85). Moreover, ETCOc appeared to be the only significant independent variable to affect the regression analysis in relation to neurodevelopmental outcome. After bootstrapping , the results showed that ETCOc remained significant (p=0.042; F=1.86; df=7).
The receiver operating characteristic curve on the first day of life for ETCOc had an area under the curve of 0.752 (95% CI 0.631-0.830) and is shown in Figure 2. The computed cut-off value for ETCOc related to adverse neurodevelopmental outcome was 2.0ppm. The sensitivity and specificity were 93% and 53% respectively . Positive and negative predictive values of ETCOc to diagnose adverse neurodevelopmental outcome were 43% and 85% respectively.
Discussion
The present study showed that there is a negative correlation between the concentration of exhaled CO during the first day of life in very preterm infants and their neurodevelopmental outcome, which was determined by using the Griffiths scales at 3 years 6 months of age. The question remains as to whether this is merely an association or whether there may be a causal relationship.
Considering elevated ETCOc values to be a valid and sensitive early indicator of respiratory diseases in infants,17 and particularly of severe RDS and BPD,6,8 this parameter has been proposed to mirror the intensity of perinatal proinflammatory activity and oxygen toxicity.1 ,6,27,28 Recently, Gagliardi et al.11 analysed the relationship between BPD and brain white matter damage in a large cohort of very preterm infants admitted to 12 hospitals in northern Italy. They indeed found an association between BPD and an increased risk of white matter damage. It was suggested that there is probably a complex relationship due to shared ante- and perinatal risk factors and causal pathways, but that evidence for an independent pathophysiological contribution of BPD to the aetiology of white matter damage is far from overwhelming . Capoluongo et al.29 suggested that there might be a link between insulin-like growth factor 1 and the occurrence of BPD and brain damage, but refrained from speculating whether this link is a functional one or merely an indirect connection. A report by Hansen-Pupp et al.27 suggested the former possibility , since perinatal proinflammation was linked to the insulin-like growth factor 1, as indicated by the association between elevated levels of IL-6 and IL-8 at 72 hours of life and lower insulin like growth factor 1 levels and an increased risk of brain damage. In this respect, a previous study by our own group is noteworthy. In this study12 we established a relationship between severe RDS in very preterm infants with elevated levels ofIL-6, IL-8, and MDA (and ETCOc, unpublished data) and the subsequent (early) development of severe intraventricular haemorrhages. Other investigators, however, have been unable to show an unequivocal independent relationship between BPD and (white matter) brain damage.30 They suggest that other factors associated with (severe) RDS and BPD, such as postnatal steroid treatment, increase the risk for adverse neurodevelopmental outcome. 9
The present study certainly has some limitations, such as the rather small sample size and the fact that only a few extremely preterm infants (gestational age <28wks) were involved. Moreover, although we found significantly higher ETCOc values at day 1 in the children with adverse outcome, proinflammatoη factors such as IL-6, IL-8, and MDA, an indicator of oxidative stress, were not significantly higher in the adverse outcome group. Therefore, the suggestion that increased perinatal proinflammatoηr cytokine production contributes to adverse neurodevelopmental outcome has still to be validated.
Inconclusion, the vast majority of infants with adverse neurodevelopmental outcome at 3 years 6 months of age exhibit increased ETCOc values within the first 24 hours of life, and this may be related, probably directly, to severe respiratory complications and possibly intraventricular haemorrhages. An ETCOc value less than 2.0ppm within the first 24 hours of life is highly predictive of a favourable neurodevelopmental outcome at 3 years 6 months of age.
Acknowledgments
This work was supported by the National Institutes of Health grant MO L RR000070-45 and the Hess Research Fund, the Mary L. Johnson Research Fund, and the H.M. Lui Research Fund. We thank Natus Medical, Inc., San Carlos, CA, USA, for supplying the CO-Stat End Tidal Breath Analyzer with disposables. We also thank Floris Groenendaal and Cuno Uiterwaal for their input concerning the statistics, and Roland Marges for his technical assistance.
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List of Abbreviations
BPD Bronchopulmonary dysplasia
ETCOc End-tidal carbon monoxide
IL Interleukin
MDA Malondialdehyde
RDS Respiratory distress syndrome
TAFα Tumour necrosis factor alpha
What this paper adds
• End-tidal carbon monoxide value less than 2.0ppm within the first 24 hours of life is highly predictive of a favourable neurodevelopmental outcome at 3 years 6 months of age.
• The vast maiority of infants with adverse neurodevelopmental outcome have increased values of end-tidal carbon monoxide (>2.0ppm ) within the first 24 hours of life.
• End-tidal carbon monoxide can be measured reliably and in a non-invasive way in ventilated and non-ventilated very preterm infants.