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JAMA Pediatrics Journal Club Slides: Surgery and Neurodevelopmental Outcome of VLBW Infants.
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JAMA Pediatrics Journal Club Slides:Surgery and NeurodevelopmentalOutcome of VLBW Infants Morriss FH Jr, Saha S, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.Surgery and neurodevelopmental outcome of very low-birth-weight infants. JAMA Pediatr. Published online June 16, 2014. doi:10.1001/jamapediatrics.2014.307.
Introduction • Background • Administration of general anesthetic agents to developing animals induces increased neuroapoptosis and subsequent neurocognitive or behavioral deficits. Both neurons and oligodendrocytes are affected. • The peak vulnerability to neuroapoptotic injury in animal experiments occurs at a stage of brain development equivalent to early gestation through infancy in humans. • Spinal anesthesia in developing animals does not produce increased neuroapoptosis and is not associated with recognized adverse outcomes. • Animal studies and some clinical studies raise concern about surgery with general anesthesia in neonates. • Study Objective • To assess theassociation between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low- birth-weight infants at 18-22 months’ corrected age.
Methods • Study Design • Retrospective cohort analysis of patients enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998-2009 and evaluated at 18-22 months’ corrected age. • Setting • 22 Academic neonatal intensive care units. • Patients • Inclusion criteria were birth weight 401-1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. A total of 12 111 infants were included in analyses (87% of those eligible). • Exposure of Interest • Surgical procedures; surgery was also classified by expected anesthesia type as major surgery (general anesthesia) or minor surgery (nongeneral anesthesia).
Methods • Outcomes • Primary outcome: Risk-adjusted death or neurodevelopmental impairment at 18-22 months’ corrected age was estimated by multivariable logistic regression analyses in which either a 2- or 3-level surgery variable was the predictor of interest. Additional covariables were other risk factors as well as a propensity score adjustment. • Risk-adjusted neurodevelopmental impairment at 18-22 months’ corrected age among survivors was estimated by similarly constructed multivariable logistic regression analyses. • Multivariable linear regression analyses were performed for the adjusted means of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006. • Cognitive composite scores of the Bayley Scales of Infant Development, Third Edition, and Gross Motor Function Classification System levels were also evaluated.
Methods • Limitations • Classification of surgery patients into subgroups is not confirmed by documented type of anesthesia. • Known and suspected risk factors for neurodevelopmental impairment in very low-birth-weight infants, some associated with surgery, were not available in the database. These include: • Type and duration of exposure to anesthetic agents. • Effects of pharmacologic agents other than anesthetics, such as analgesics, administered to surgery patients. • Physiological alterations associated with surgery, such as stress and alterations in blood pressure and/or temperature. • Retrospective cohort study design does not consider unknown confounding factors.
Results • There were 2186 major and 784 minor surgery patients and 9141 patients who did not undergo surgery. • The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). • There were increasing risk-adjusted odds of death or neurodevelopmental impairment with increasing number of separate surgeries. • For patients who had major surgery compared with those who did not undergo surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87).
Results • For patients who had major surgery compared with those who had minor surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.45 (95% CI, 1.14-1.85). • There was no significant difference in risk of death or neurodevelopmental impairment for patients who had minor surgery compared with those who did not undergo surgery. • Among survivors who had major surgery compared with those who did not undergo surgery, the risk-adjusted odds ratio for neurodevelopmental impairment was 1.56 (95% CI, 1.26-1.93) and the risk-adjusted mean Mental Developmental Index and mean Psychomotor Developmental Index values were lower.
Results • A sensitivity analysis in which the classification of patients who had procedures to repair inguinal hernia, gastroschisis, or omphalocele was changed from minor to major surgery resulted in no significantly increased adjusted risk of death or neurodevelopmental impairment for major surgery patients compared with patients who did not undergo surgery, suggesting a relatively low adverse risk for this group of procedures as well as effect modification.
Results Model 3: Multivariable Logistic Regression Analysis of the Primary Outcome of Death or Neurodevelopmental Impairment With 3-Level Surgery Predictor Variable Other covariables include small for gestational age, male, multiple birth cohort, white race, 5-min Apgar score ≤3, antenatal corticosteroid exposure, postnatal corticosteroid exposure, seizures, severe intracranial hemorrhage and/or cystic periventricular leukomalacia, bronchopulmonary dysplasia, sepsis and/or meningitis, necrotizing enterocolitis, patent ductus arteriosus (excluding surgically closed patients), highest educational level attained by primary caregiver, birth year, inborn, center, and propensity scores for major and minor surgery.
Comment • Very low-birth-weight infants who underwent surgical procedures during their postnatal hospitalizations had increased adjusted risk of death or neurodevelopmental impairment at 18-22 months’ corrected age, and survivors had increased adjusted risk of neurodevelopmental impairment. Classification to major or minor surgery groups based on expected type of anesthesia resulted in increased adjusted risk of death or neurodevelopmental impairment for those classified as major, but not for those classified as minor surgery patients. The adjusted risk of neurodevelopmental impairment among survivors was increased for major surgery patients. • However, when procedures to repair inguinal hernia, gastroschisis, or omphalocele were reclassified from minor to major surgery, we observed effect modification, ie, the adverse risk for the major surgery group became insignificant, suggesting a relatively low adverse risk for this group of procedures that may be a consequence of length of exposure to anesthetic agents or other factors.
Comment • This was a retrospective cohort study in which we were able to adjust for a large number of potentially confounding variables, but important known factors that are associated with the outcomes were not available. The type of anesthesia used in each procedure was not documented, and the classification into major and minor groups may be associated with factors other than anesthesia type that are responsible for the observed results. • This analysis supports the concern that surgery usually requiring general anesthesia during a vulnerable period of infancy has an adverse effect on neurodevelopmental outcome and extends that concern to very low-birth-weight neonates. On the other hand, this analysis failed to demonstrate increased risk of neurodevelopmental impairment after surgical procedures that may have been performed under anesthesia other than general anesthesia.
Contact Information • If you have questions, please contact the corresponding author: • Frank H. Morriss Jr, MD, MPH, Department of Pediatrics, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242 (email@example.com). Funding/Support • The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network’s Generic Database Study through cooperative agreements. Conflict of Interest Disclosures • None reported.