Hugues Patural

Preterm births: Can neonatal pain alter the development of endogenous gating systems?

Prematurity is known to affect the development of various neurophysiological systems, including the maturation of pain and cardiac circuits. The purpose of this study was to see if numerous painful interventions, experienced soon after birth, affect counterirritation‐induced analgesia (triggered using the cold pressor test) later in life. A total of 26 children, between the ages of 7 and 11 participated in the study. Children were divided into three groups, according to their birth status (i.e., term‐born, born preterm and exposed to numerous painful interventions, or born preterm and exposed to few painful interventions). Primary outcome measures were heat pain thresholds, heat sensitivity scores, and cardiac reactivity. Results showed that preterm children and term‐born children had comparable pain thresholds. Exposure to conditioning cold stimulation significantly increased heart rate and significantly decreased the thermal pain sensitivity of term‐born children. These physiological reactions were also observed among preterm children who were only exposed to a few painful interventions at birth. Changes in heart rate and pain sensitivity in response to conditioning cold stimulation were not observed in preterm children that had been exposed to numerous painful procedures during the neonatal period. These results suggest that early pain does not lead to enhanced pain sensitivity when premature babies become children, but that their endogenous pain modulatory mechanisms are not as well developed as those of children not exposed to noxious insult at birth. Greater frequency of painful procedures also dampened the rise in heart rate normally observed when experimental pain is experienced.

Autonomic nervous system activity in premature and full-term infants from theoretical term to 7 years

The premature population reaching theoretical term suffers from a major deficit in autonomic nervous system (ANS) activity, as can be seen from heart rate variability indices. Whether this autonomic function recovers in the long term is not yet established. Thus, we analyzed and compared ANS activity indices, at birth or at the time of the theoretical term, and at ages 2-3 and 6-7 years, in two populations: a group of 30 premature children and a reference group of 14 full-term age-matched newborns. Using Fourier Transform analysis, we studied 24-h ECG Holter recordings to establish heart rate variability indices: Ptot, VLF, LF, HF, ratio LF/HF, LFnu, HFnu. In the neonatal period, sympathetic and even more markedly, parasympathetic activities were very low in prematures compared to the reference full-term group. At ages 2-3 and 6-7 years, prematures had recovered and had similar ANS activity as the full-term group. These data suggest a fast ANS maturation in prematures during the two first years of life, with a higher speed of recovery for the parasympathetic arm. Furthermore, compared evolution shows a faster ANS maturation in premature. Potential mechanisms are discussed.

Autonomic cardiac control of very preterm newborns: A prolonged dysfunction

BACKGROUND Autonomic nervous system (ANS) activity is fundamental to infant health. ANS activity of preterm newborns seems to be reduced at term equivalent age, but follow-up of ANS activity has rarely been performed in that population during the weeks after birth. The aim of the study was to perform such a follow-up in preterm newborns of different gestational ages, up to their term equivalent ages. METHODS Prolonged electrocardiographic recordings were prospectively performed in a group of 39 premature newborns, each week, up to term equivalent age before discharge. Control values were obtained from a group of 19 full-term newborns, recorded at the first week of their life. ANS indices were calculated from recordings during quiet sleep periods by spectral-domain analysis (Fourier transform): Ptot (total power), VLF (very low-frequencies), LF (low-frequencies), HF (high-frequencies), LF/HF ratio, LFnu (normalized low-frequencies) and HFnu (normalized high-frequencies) values. RESULTS Ptot, VLF, LF and HF were significantly lower in the preterm group at birth compared to the control group, while LFnu, HFnu and LF/HF ratio were not significantly different. The results were similar when comparing the control group to any ANS values at a given post-natal corrected age of preterm newborns. Furthermore, preterm newborns did not demonstrate any significant increase in ANS values from birth to theoretical term. CONCLUSION The finding of substantial reduced ANS activity and failure of maturation in preterm infants up to term equivalent age needs confirming by other research groups, and mechanisms and implications for infant health explored.

Birth prematurity determines prolonged autonomic nervous system immaturity.

Because of its multiple involvement in physiological processes, autonomic nervous system (ANS) activity, a key regulator of homeostatic control, demonstrates a progressive increase during pregnancy. The profile of its maturation, mainly in the parasympathetic arm, in premature or full term infants, may help us to better understand its pathophysiological role. We prospectively evaluated ANS maturity in a group of 23 premature (PREM) infants at their theoretical term age and in 8 full term (FT) newborns. All recordings were registered close to the theoretical full term period (from 38 to 41 weeks) for the PREM group and during the first week of life for the FT newborns. Polygraphic recordings, EEG monitoring associated with visual clinical control, and Holter ECG, were performed simultaneously. ANS indices were then calculated during quiet sleep periods, using Wavelet transform of RR (beat to beat) intervals. High frequency components were found to be significantly lower in the PREM than in the FT group (p<0.05). Furthermore, at theoretical full term age, the greater the prematurity, the lower was parasympathetic activity. Because it is easy, monitoring of parasympathetic activity may help us to understand autonomic maturation and its clinical prognostic implications.

Autonomic dysfunction with early respiratory syncytial virus-related infection.

BACKGROUND Apparent life-threatening events (ALTE) and/or prolonged apnoea have been well-documented during respiratory syncytial virus (RSV) infection in infants less than 2 months of age but fundamental mechanisms remain unclear. The possibility of a central origin for the development of severe cardiac and respiratory events encouraged us, to explore the autonomic nervous system (ANS) profile of infected infants, since ANS activity may contribute to the constellation of symptoms observed during severe forms of RSV bronchiolitis. METHODS Eight infants (2 preterm and 6 full-term) less than 2 months of age and presenting with severe and apnoeic forms of RSV infection were evaluated using non-invasive electrophysiological monitoring obtained simultaneously for approximately 2 consecutive hours, including a quiet sleep period. Eight control subjects, paired for gestational and postnatal age, were also evaluated. ANS status was monitored using electrocardiogram recordings and quantified through a frequency-domain analysis of heart rate variability (HRV). This included sympathetic (VLF and LF) and parasympathetic (HF) indices as well as a measure of baroreflex sensitivity (BRS) obtained using non-invasive continuous arterial pressure. RESULTS Regardless of gestational and postnatal age, heart rate variability components (Ptot, VLF, LF, and HF) and baroreflex components (alpha LF, alpha HF and sBR) were found to be significantly lower in the RSV-infected group than in the control group (p<0.05). CONCLUSION RSV infection in neonates is associated with profound central autonomic dysfunction. The potentially fatal consequence stresses the importance of maintaining prolonged cardiopulmonary monitoring.

Effects of simulated reflux laryngitis on laryngeal chemoreflexes in newborn lambs

It has been suggested that reflux laryngitis (RL) is involved in apneas-bradycardias of the newborn. The aim of the present study was to develop a unique RL model in newborn lambs to test the hypothesis that RL enhances the cardiorespiratory components of the laryngeal chemoreflexes (LCR) in the neonatal period. Gastric juice surrogate (2 ml of normal saline solution with HCl pH 2 + pepsin 300 U/ml) (RL group, n = 6) or normal saline (control group, n = 6) was repeatedly injected onto the posterior aspect of the larynx, 3 times a day for 6 consecutive days, via a retrograde catheter introduced into the cervical esophagus. Lambs instilled with gastric juice surrogate presented clinical signs of RL, as well as moderate laryngitis on histological observation. Laryngeal chemoreflexes were thereafter induced during sleep by injection of 0.5 ml of HCl (pH 2), ewes milk, distilled water or saline into the laryngeal vestibule via a chronic, transcutaneous supraglottal catheter. Overall, RL led to a significantly greater respiratory inhibition compared with the control group during LCR, including longer apnea duration (P = 0.01), lower minimal respiratory rate (P = 0.002), and a more prominent decrease in arterial hemoglobin saturation (SpO(2)) (P = 0.03). No effects were observed on cardiac variables. In conclusion, 1) our unique neonatal ovine model presents clinical and histological characteristics of RL; and 2) the presence of RL in newborn lambs increases the respiratory inhibition observed with LCR, at times leading to severe apneas and desaturations.

Infant botulism intoxication and autonomic nervous system dysfunction

Three infants presenting with severe cases of infantile botulism, occurring at 17, 30, and 180 days of life, respectively, are described in this report. All three infants presented with areflexive flaccid coma or apnoeas requiring prolonged ventilation. In serum, type B botulinum neurotoxin (BoNT/B) was detected in two cases and BoNT/A in the third case, confirming the diagnosis of infantile botulism. Despite constant nursing and monitoring, the recovery of motility was progressive, but finally complete. Dysautonomia, measured by recording heart rate variability (HRV), persisted beyond observable physical recovery. Dysautonomia was assessed using a time-domain analysis of the continuous electrocardiogram response (via non-invasive weekly 24h Holters), which included sympathetic (SDNN) and parasympathetic indices (RMS-SD, pNN50). In all three of our patients, we observed an initial hypotonic period and a major decrease in all HRV indices. Despite observable recovery shortly after extubation, HRV time domain indices remained altered for many weeks. Because of the close monitoring afforded by hospitalization, this change in autonomic function was not accompanied by syncope, complications arising from ventricular arrhythmia, or sudden death. Our observations have important clinical implications since they emphasize the importance of pursuing cardiopulmonary monitoring following apparent functional recovery from the BoNTs.

Sleep Trajectories Among Pregnant Women and the Impact on Outcomes: A Population-Based Cohort Study

Objectives Sleep problems and deprivation are common during pregnancy, particularly in the third trimester. Previous studies are mostly descriptive or focused on specific clinical groups and late pregnancy. We aimed to identify sleep duration trajectories during the pregnancy period, their associated factors, and impact on pregnancy and birth outcomes. Methods We studied 200 women from a mother–child cohort recruited in 2009–2011 from the French general population. We used semi-parametric models to analyze data collected through questionnaires. Results We detected three sleep duration trajectories during pregnancy: short-decreasing (<6.5h/night, 10.8% of the sample), medium-decreasing (6.5-8h/night, 57.6%), and long-increasing (>8h/night, 31.6%) trajectories. Factors associated with the short-decreasing trajectory relative to the medium-decreasing trajectory were older age (odds-ratio/year = 1.13 [95%Confidence-Interval 1.00-1.29]) and working > 28 weeks of gestational age (odds-ratio = 0.30 [0.10–0.90]). Sleep duration during pregnancy in this trajectory group was modified by insomniac symptoms (regression coefficient/trimester = −0.74 [Standard-Error 0.12]) and naps (regression coefficient/trimester = 0.58 [0.25]). Restless legs syndrome was the only factor associated with the long-increasing trajectory and decreased sleep duration (regression coefficient/trimester = −0.88 [0.25]). Assisted delivery (i.e. cesarean section and/or instrumental delivery) and post-partum depression were more frequent among women with the short-decreasing and long-increasing trajectories whereas cesarean section alone was more prevalent among those with the short-decreasing trajectory. Proportion of premature births was higher in the short-decreasing trajectory group. Birth-weight-z-score was lower in the long-increasing trajectory group. Conclusion We identified sleep trajectories among pregnant women with specific risk factors that could affect both pregnancy and birth outcomes. Taking these into consideration could improve both maternal and child health.

Postnatal autonomic activity in the preterm lamb

BACKGROUND Early postnatal abnormalities of autonomic nervous system (ANS) activity, including at baseline and following cardiorespiratory challenge, are involved in apneas-bradycardias of prematurity, apparent life-threatening events of infancy and sudden infant death syndrome. Literature data suggest that baseline ANS activity does not mature normally after premature birth. OBJECTIVES This study performed in preterm lambs was aimed at assessing ANS maturation at baseline and following laryngeal chemoreflexes (LCR), a group of reflexes triggered by the contact of liquids with the laryngeal mucosa. METHODS Heart rate variability (HRV) and baroreflex sensitivity (BRs) were measured at baseline and after LCR during polysomnographic recordings performed in five non-sedated lambs born 15 days prematurely. Laryngeal chemoreflexes were induced by distilled water or acid (pH 2) during sleep and wakefulness on postnatal days 7 (D7) and 14 (D14, full-term equivalence). RESULTS While the life-threatening cardiorespiratory events of the LCR observed at D7 were no longer present at D14, baseline and post-LCR HRV and BRs indices were significantly lower at D14 compared to D7 (up to p<0.001). These results suggest that an initial autonomic overactivity was present at D7 and normalized at D14. CONCLUSION The autonomic cardiac and baroreflex control appears to follow a specific evolution in the preterm compared to the full-term newborn lamb, with an important initial autonomic stress, which normalizes at an age equivalent to full-term. Potential relevance of these findings in relation to anomalies of cardiac control in the early postnatal period, such as apneas-bradycardias of prematurity, apparent life-threatening events of infancy and sudden infant death syndrome, awaits further studies.

Two new mutations of the CLMP gene identified in a newborn presenting congenital short-bowel syndrome

Congenital short-bowel syndrome (CSBS) is a rare neonatal pathology associated with poor prognosis and high mortality rate. We describe a newborn presenting CSBS intestinal malrotation and chronic intestinal pseudo-obstruction syndrome (CIPS), compound heterozygous for two previously unreported heterozygous mutations in Coxsackie and adenovirus receptor-like membrane protein (CLMP) gene, one in intron 1 (c.28+1G>C), the other on exon 4 (c502C>T, p.R168X). Both mutations are predicted to be pathogenic, leading to impaired splicing and the appearance of a premature stop codon, respectively. Our case is remarkable in that it concerns two heterozygous truncating mutations associated with a good clinical prognosis with a favorable cerebral and gastrointestinal outcome and a substantial enteral input at 8 months of age, despite a small intestine measuring only 35cm.