Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Ranger, Manon; Chau, Cecil M. Y.; Garg, Amanmeet; Woodward, Todd S.; Beg, Mirza Faisal; Björnson, Bruce; Poskitt, Kenneth J.; Fitzpatrick, Kevin M.; Synnes, Anne; Miller, Steven P.; Grunau, Ruth E.

doi:10.1371/journal.pone.0076702

Cited by 236 publications

(170 citation statements)

References 81 publications

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“…Comparing the MRI scans of the children born preterm with those of healthy controls, which were obtained for other follow-up studies of our department [23], we found no differences in either cortical thickness or brain volumes after correction for age, gender, total brain volume, and multiple testing (data not shown). We expected thinning of the cortex, as this was found in a study in 42 children born preterm with a median age of 7.8 years (IQR 7.7-8) [13]. The explanation possibly lies in the fact that the median gestational age in our study group was higher: 31.1 weeks (range 26.1-36.3) versus 29.7 weeks (range 24-32).…”

Section: Discussionmentioning

confidence: 53%

“…A greater number of invasive procedures in children born preterm are associated with abnormalities in white matter brain structure associated with lower intelligence [12]. Pain-related stress is associated with a thinner cortex [13] and with changes in functional cortical activity that are negatively correlated with visual-perceptual functioning during childhood [14]. …”

Section: Introductionmentioning

confidence: 99%

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Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain?

Bosch¹,

White

Marroun

et al. 2015

Neonatology

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Background: Traditionally, 10 years ago, children born preterm often routinely received morphine, especially during mechanical ventilation. Studies in neonatal rats, whose stage of brain development roughly corresponds to that of children born preterm, found negative long-term effects after pain and opioid exposure. Objectives: We studied possible effects of prematurity, procedural pain and opioids in humans 10 years later. We hypothesized that these factors would negatively influence neurobiological, neuropsychological and sensory development later in life. Methods: We included 19 children born preterm who as neonates participated in an RCT on the short-term effects of morphine administration and who previously participated in our follow-up studies at ages 5 and 8/9 years. We assessed associations between brain morphology (n = 11), neuropsychological functioning (n = 19) and thermal sensitivity (n = 17) and prematurity, opioid exposure and neonatal pain. Results: Significant correlations (coefficients 0.60-0.85) of gestational age, number of painful procedures and morphine exposure with brain volumes were observed. Significant correlations between these factors and thermal sensitivity were not established. Neuropsychological outcome was significantly moderately correlated with morphine exposure in only two subtests, and children performed in general ‘average' by Dutch norms. Conclusions: Although prematurity, opioid exposure and neonatal pain were significantly associated with brain volume, no major associations with neuropsychological functioning or thermal sensitivity were detected. Our findings suggest that morphine administration during neonatal life does not affect neurocognitive performance or thermal sensitivity during childhood in children born preterm without brain damage during early life. Future studies with larger sample sizes are needed to confirm these findings.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain?

Bosch¹,

White

Marroun

et al. 2015

Neonatology

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“…Caution is increased for preterm infants because their neurodevelopment may be compromised by inappropriate exposure to either stress or drugs. For example, in preterm infants born < 32 wk gestation, the degree of neonatal pain and stress correlated with cortical thickness at 7 y of age, raising concerns about the long-term negative effects of early pain exposure (28). The increasing use of off-label DEX for neonatal sedation compels examination of the consequences of prolonged early DEX exposure.…”

Section: Dex Effects In Hypothermic Neonatal Ratsmentioning

confidence: 99%

Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats

et al. 2015

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Background:The α2-adrenergic agonist dexmedetomidine (DEX) is increasingly used for prolonged sedation of critically ill neonates, but there are currently no data evaluating possible consequences of prolonged neonatal DEX exposure. We evaluated the pharmacokinetics and histological consequences of neonatal DEX exposure. Methods: DEX was administered (s.c.) to naive (uninjured) neonatal Lewis rats to provide acute (25 µg/kg, ×1) or prolonged (25 µg/kg three times daily, ×2 or ×4 d) exposure. Therapeutic hypothermia was simulated using a water-cooled blanket. Cranial temperatures were measured using an infrared thermometer. DEX concentrations were measured by LC-MS in plasma and homogenized brainstem tissue for pharmacokinetic analysis. Cortex, cerebellum, and brainstem were evaluated for evidence of inflammation or injury. results: Prolonged neonatal DEX exposure was not associated with renal or brain pathology or indices of gliosis, macrophage activation, or apoptosis in either hypothermic or control rats. Plasma and brain DEX concentrations were tightly correlated. DEX peaked within 15 min in brain and reduced cranial temperature from 32 to 30 °C within 30 min after injection in cooled rats. conclusion: Prolonged DEX treatment in neonatal rats was not associated with abnormal brain histology. These data provide reassuring preliminary results for using DEX with therapeutic hypothermia to treat near-term brain injury. i n critically ill neonates, pain-related stress affects developmental outcomes, so appropriate pain management is paramount (1). Opioid infusions, sometimes in combination with benzodiazepines, are commonly administered with the intent to decrease pain, agitation, and stress responses in neonates exposed to frequent procedures, during mechanical ventilation, or during therapeutic cooling for hypoxic-ischemic encephalopathy (HIE). However, opioid and benzodiazepine exposure may produce neuroapoptosis and neurodevelopmental abnormalities (2,3). To reduce opioid exposure, alternative pain medications are needed, but few of the analgesics used in adults have been tested in neonates. Dexmedetomidine (DEX) has recently become a popular analgesic used in adult critical care (4).A selective α-2 adrenoceptor agonist, DEX produces analgesic and sedative effects that can synergize with other analgesics (5,6). In randomized studies of adults, DEX lowers dosing requirements for adjunctive sedatives, shortens hospital stay, decreases psychosis, and may improve posthospitalization memory and cognitive function (7-9). It is recommended for short-term use only, less than 48 h. Minimal efficacy, pharmacokinetic, and safety data exist for neonates. Despite limited testing and without current Food and Drug Administration approval, the off-label use of DEX in pediatric and neonatal intensive care units is increasing (10-12). Since DEX can provide sedation and prevent shivering, it is a viable alternative to opioids for neonatal intensive care units patients undergoing therapeutic hypothermia as treatment for HIE. Con...

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“…For example, when preterm newborns experience pain-related stress, there is significantly thinner cortex in a variety of cerebral regions, but predominately in the frontal and parietal lobes [26]. …”

Section: Preterm Brain Injurymentioning

confidence: 99%

The Vulnerable Newborn Brain: Imaging Patterns of Acquired Perinatal Injury

Ferriero¹

2016

Neonatology

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Background: Over the past two decades, imaging techniques have allowed for better visualization of the newborn brain. This has enabled us to detect patterns, understand mechanisms and guide diagnosis and treatment. Objectives: The purpose of this review is to discuss imaging characteristics of acquired perinatal brain injury. Methods: Through literature review and the author's research, this review assesses published data on the distinct imaging patterns that occur in the neonatal period due to acquired brain insults. Results: In the term brain, susceptibility to hypoxia-ischemia, hypoglycemia and hyperbilirubinemia results in unique patterns of injury. Stroke commonly occurs in the newborn period. Infections, especially viral, have distinct patterns of white matter injury. In the preterm brain, white matter injury occurs commonly and is affected by postnatal growth, stress and infection. The cerebellum is uniquely vulnerable during this period, with resultant hemorrhages in almost half of preterm infants. Cerebellar growth is affected by intraventricular hemorrhage, drugs and placental pathology. Periventricular hemorrhagic infarction is the most serious consequence of the spectrum of intraventricular hemorrhage and results in profound disabilities. Conclusions: Taken together, the acquired perinatal brain injuries can have lifelong devastating consequences, so the search for therapies must continue.

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Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Cited by 236 publications

References 81 publications

Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain?

Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain?

Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats

The Vulnerable Newborn Brain: Imaging Patterns of Acquired Perinatal Injury

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