Abstract
Background. Infants routinely undergo prolonged sedation with opioids and benzodiazepines for proper clinical management, as part of the standard of care. Recent evidence suggests that prolonged exposure to pain medication may have negative effects on infant brain development. The clinical impact of such treatment on the full-term infants is largely unknown.\r Hypothesis. Prolonged sedation with opioids and benzodiazepines in full-term patients is associated with increased incidence of brain abnormalities as per brain MRI scan in comparison to healthy controls.\r \r Methods. We compared full-term patients less than 12 months of age with healthy controls as per IRB approval at Boston Children’s Hospital. We quantified the amounts of drugs used for prolonged sedation management that included opioids (fentanyl, morphine, methadone) and benzodiazepines (midazolam, lorazepam). End-point analyzes included: (1) length of sedation and weaning (days), (2) total treatment doses per patient (mg/kg/day), (3) average daily doses during sedation and weaning (mg/kg/day ± SD), (4) number of anesthesia events. To correlate these values with neurological outcomes, we further quantified (5) number of incidental findings on brain MRI reports, and (6) estimated cerebrospinal and brain volumes using MANTiS segmentation. Pearson’s correlation coefficient was used to measure the linear relations between the different variables analyzed.\r \r Results. Morphine and midazolam were the two drugs used the most frequently for prolonged sedation and were administered at the highest doses. Neuroradiology reports showed abnormalities in extra-axial space, parenchyma, and/or white matter structures that were not present in the controls. Our data show significant positive linear relationships for the average daily dose of administered morphine (r=0.933, p=0.002) and midazolam (r=0.810, p=0.03) with the number of neuroradiological abnormalities. Although there is a positive trend between the average daily dose of morphine (r=0.573, p=0.18) and midazolam (r=0.548, p=0.20) with the amount of cerebrospinal fluid, as well as a negative trend between the average daily dose of morphine (r=-0.561, p=0.19) and midazolam (r=-0.521, r=0.23) with the brain volume, none were significant. Additional factors such as the number of anesthesia events (r=0.398, p=0.37) and days of sedation (r=0.397, p=0.37) are not significantly correlated to the number of neuroradiological abnormalities. The number of anesthesia events (r=-0.040, r=0.93) and days of sedation (r=0.189, p=0.69) have no relationship to the amount of cerebrospinal fluid. Similary, the number of anesthesia events (r=0.065, p=0.89) and days of sedation (r=-0.186, p=0.69) have no relationship to brain volume. \r \r Conclusions. Prolonged sedation with morphine and midazolam is significantly associated with an increased incidence of incidental neuroimaging findings. In contrast, there is no correlation to increased cerebrospinal fluid and decreased brain volumes in full-term infants. Given the current standard of care using these drugs, further studies should investigate how prolonged sedation with opioids and benzodiazepines can affect brain development and its long-term sequelae.