Gene expression in the intestine of newborn piglets after hypoxia-reoxygenation.

BACKGROUND: In preterm infants, intestinal hypoxia may partly contribute to the pathophysiology of necrotizing enterocolitis through changes in gene expression. Splanchnic hypoxia can be detected with monitoring of regional splanchnic oxygen saturation (rsSO2). Using a piglet model of asphyxia, we aimed to correlate changes in rsSO2 to gene expression. METHODS: Forty-two newborn piglets were randomized to control or intervention groups. Intervention groups were subjected to hypoxia until they were acidotic and hypotensive. Next, they were reoxygenated for 30 min according to randomization, i.e., 21% O2, 100% O2, or 100% O2 for 3 min followed by 21% O2, and observed for 9 h. We continuously measured rsSO2 and calculated mean rsSO2 and variability of rsSO2 (rsCoVar = SD/mean). Samples of terminal ileum were analyzed for mRNA expression of selected genes related to inflammation, erythropoiesis, fatty acid metabolism, and apoptosis. RESULTS: The expression of selected genes was not significantly different between control and intervention groups. No associations between mean rsSO2 and gene expression were observed. However, lower rsCoVar was associated with the upregulation of apoptotic genes and the downregulation of inflammatory genes (P < 0.05). CONCLUSION: Our study suggests that hypoxia and reoxygenation cause reduced vascular adaptability, which seems to be associated with the upregulation of apoptosis and downregulation of inflammation. IMPACT: Our results provide important insight into the (patho)physiological significance of changes in the variability of rsSO2. Our findings may advance future research and clinical practice regarding resuscitation strategies of preterm infants.

Splanchnic oxygen saturation during reoxygenation with 21% or 100% O2 in newborn piglets.

BACKGROUND: Increasing evidence recognizes the harm of excess oxygen to lungs, eyes, and brain of preterm infants, but not yet to the intestine. We assessed changes in splanchnic oxygenation during reoxygenation with 21% compared to 100% O2 in a newborn piglet model of perinatal asphyxia. METHODS: We randomized 25 piglets to control or intervention. Intervention groups underwent global hypoxia until acidosis and hypotension occurred. Piglets were reoxygenated for 30 min with 21% or 100% O2 and observed for 9 h. We continuously measured regional splanchnic oxygen saturation (rsSO2) using near-infrared spectroscopy (NIRS). We calculated mean rsSO2 and rsCoVar (as SD/mean). We measured PaO2 and SaO2, sampled from the right carotid artery. RESULTS: Reoxygenation after global hypoxia restored rsSO2. Reoxygenation with 100% O2 increased rsSO2 to values significantly higher than baseline. In intervention groups, rsCoVar decreased during observation compared to baseline. We found a correlation between rsSO2 and PaO2 (r = 0.420, P < 0.001) and between rsSO2 and SaO2 (r = 0.648, P < 0.001) in pooled data from the entire experiment. CONCLUSION: Reoxygenation after global hypoxia improves splanchnic oxygenation, but is associated with reduced variability of rsSO2. Reoxygenation with 100% O2 exposes the intestine to hyperoxia. Splanchnic NIRS is able to detect intestinal hypoxia and hyperoxia. IMPACT: Splanchnic oxygenation improves during reoxygenation after global hypoxia, though reoxygenation with 100% O2 exposes the intestine to hyperoxia. Decreased variability of splanchnic oxygenation several hours after hypoxia and reoxygenation seems to be independent of the resuscitation strategy, and may indicate intestinal injury. Splanchnic NIRS monitoring was able to detect intestinal hypoxia and exposure to hyperoxia, as evidenced by a strong correlation between splanchnic oxygenation and arterial oxygen content.

Regional splanchnic oxygen saturation for preterm infants in the first week after birth: reference values.

BACKGROUND: Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rsSO2), but solid reference values are scarce. We aimed to establish reference values of rsSO2 for preterm infants during the first week after birth, both crude and modeled based on predictors. METHODS: We included infants with gestational age (GA) <32 weeks and/or birth weight <1200 g. We excluded infants who developed necrotizing enterocolitis or sepsis or who died. In the first week after birth, we determined a daily 2-h mean of rsSO2 to assess its associations with sex, GA, postnatal age (PNA), small-for-gestational age (SGA) status, patent ductus arteriosus, hemoglobin, nutrition, and head circumference at birth and translated those into a prediction model. RESULTS: We included 220 infants. On day 1, the mean ± SD rsSO2 value was 48.2% ± 16.6. The nadir of rsSO2 was on day 4 (38.7% ± 16.6 smoothed line) to 5 (37.4%±17.3, actual data), after which rsSO2 increased to 44.2% ± 16.6 on day 7. The final model of the reference values of rsSO2 included the following coefficients: rsSO2 = 3.2 - 7.0 × PNA + 0.8 × PNA2 - 4.0 × SGA + 1.8 × GA. CONCLUSIONS: We established reference values of rsSO2 for preterm infants during the first week after birth. GA, PNA, and SGA affect these values and need to be taken into account. IMPACT: Regional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study.

Maturation of Intestinal Oxygenation: A Review of Mechanisms and Clinical Implications for Preterm Neonates.

Nutrient requirements of preterm neonates may be substantial, to support growth and maturation processes in the presence of challenging post-natal circumstances. This may be accompanied by substantial intestinal oxygen requirements. Preterm neonates may not be able to meet these oxygen requirements, due to a developmental delay in intestinal oxygenation regulation mechanisms. This review summarizes the available literature on post-natal maturation of intestinal oxygenation mechanisms and translates these changes into clinical observations and potential implications for preterm neonates. The different mechanisms that may be involved in regulation of intestinal oxygenation, regardless of post-natal age, are first discussed. The contribution of these mechanisms to intestinal oxygenation regulation is then evaluated in newborn and mature intestine. Finally, the course of clinical observations is used to translate these findings to potential implications for preterm neonates.

Longitudinal growth and emotional and behavioral problems at age 7 in moderate and late preterms.

OBJECTIVES: Moderately and late preterm children (MLPs, 32.0-36.9 weeks gestational age) have a greater risk of poorer growth. This seems to be associated with poorer neuropsychological functioning. Evidence is limited on whether this also holds for emotional and behavioral (EB) problems. Therefore, we assessed whether longitudinal growth from birth until age 7 was associated with EB problems at age 7 in MLPs. STUDY DESIGN: This study was part of the Longitudinal Preterm Outcome Project, a prospective cohort study. Data on growth (height, weight, head circumference, and extent of catch-up growth) were obtained from assessments from birth until age 7. EB problems were assessed at age 7 with the Child Behavior Checklist. We assessed whether growth and EB problems were associated using logistic regression analyses, adjusting for multiple birth, parity, and socioeconomic status. RESULTS: We included 248 MLPs. Median gestational age was 34 weeks (interquartile range: 33-35 weeks). Mean birth weight was 2.2 kg (standard deviation: 0.5 kg). Postnatal growth measures were below the Dutch reference norm. EB problems were more prevalent in MLPs than in the general Dutch population. Generally, we found no associations between growth and EB problems; odds ratios ranged from 0.20 to 2.72. CONCLUSIONS: In MLPs, postnatal growth from birth until age 7 was not associated with EB problems at age 7. Poorer growth thus seems to relate to neuropsychological problems, but not to EB problems. This suggests that the etiologies of these problems differ at least partially.

Longitudinal Growth and Neuropsychological Functioning at Age 7 in Moderate and Late Preterms.

OBJECTIVE: To determine the association between longitudinal growth measures (height, weight, head circumference, and extent of catch-up growth) and neuropsychological functioning at 7 years in moderately and late preterm children. METHODS: This study was part of a prospective, community-based cohort study. Data on growth were obtained from records on routine assessments in well-child centers until age 4 years and in a research setting at 7 years. Neuropsychological functioning was assessed at age 7 years. We assessed associations of growth with neuropsychological functioning and determined odds ratios for impaired neuropsychological functioning. All analyses were corrected for maternal education. RESULTS: We included 234 children. Median gestational age was 34 weeks (P25-75: 33-35 weeks), and mean birth weight was 2.2 kg (± 0.5 kg). Short stature at all ages was associated with poorer motor, IQ, and attention scores and led to increased risks of impaired motor skills and low IQ. Lower weight at 1 and 4 years was associated with poorer IQ scores. Increased weight gain between age 4 and 7 years was, however, associated with poorer motor, IQ, and attention scores. Decreased head circumference gain in the first year of life was associated with poorer motor and attention scores and led to an increased risk of impaired motor and attention skills. CONCLUSIONS: In moderately and late preterm children, poorer growth in the first 7 years is associated with poorer neuropsychological functioning. Regarding height, short stature was also associated with a higher likelihood of clinically relevant impaired neuropsychological functioning.