514026
research-article2013
AOPXXX10.1177/1060028013514026Lammers et alLammers et al
Research Report
Association of Fentanyl With Neurodevelopmental Outcomes in Very-Low-Birth-Weight Infants
Annals of Pharmacotherapy 2014, Vol. 48(3) 335–342 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013514026 aop.sagepub.com
Erin M. Lammers, PharmD, BCPS1, Peter N. Johnson, PharmD, BCPS2, Kimberly D. Ernst, MD, MSMI, FAAP3, Tracy M. Hagemann, PharmD, FCCP, FPPAG2, Shelley M. Lawrence, MD, MS3, Patricia K. Williams, MD3, Michael P. Anderson, PhD4, and Jamie L. Miller, PharmD, BCPS2
Abstract Background: Opioids are commonly used in the neonatal intensive care unit (NICU). Negative neurodevelopmental effects in the short-term setting have been associated with opioids ; however, long-term studies have been limited. Objective: The primary objective was to determine if there is a dose relationship between fentanyl and neurodevelopmental outcomes, as measured by Bayley Scales of Infant and Toddler Development (Bayley-III) composite scores for language, cognition, and motor skills. Secondary objectives included comparison of Bayley-III scores and neurodevelopmental impairment classification based on fentanyl exposure. Methods: A retrospective evaluation of 147 very-low-birth-weight infants with Bayley-III scores obtained at a chronological age of 6 months to 2 years at clinic follow-up was conducted. Univariate and multivariable linear regression analyses were used to determine if there was a dose-related association between fentanyl and neurodevelopmental outcomes. To evaluate secondary outcomes, patients were divided based on cumulative fentanyl dose (“high-dose” versus “low/no-dose”). Results: The univariate analysis found a statistically significant decrease in cognition (P = .034) and motor skills scores (P = .006). No association was found in the multi-variable regression between fentanyl cumulative dose and Bayley-III scores. There was a significant decrease in the motor skills score between the high-dose versus low/no-dose group, 94 ± 20 versus 102 ± 15, respectively (P = .026); however, no statistical differences were noted for language or cognition scores or neurological impairment classification. Conclusions: When controlling for other variables, the cumulative fentanyl dose did not correlate with neurodevelopmental outcomes. Further evaluation of benefits and risks of opioids in premature infants are needed. Keywords opioid, fentanyl, midazolam, neurodevelopment, premature, neonate
Introduction Opioid analgesics are commonly used in the neonatal intensive care unit (NICU) for procedural pain, postoperative pain, and sedation with prolonged mechanical ventilation.1,2 A survey of neonatologists revealed that opioids are used to treat pain resulting from medical procedures (eg, central line or chest tube insertion) in more than 90% of patients.3 Untreated pain and agitation in the premature neonate has been associated with negative neurological outcomes, including intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL).4 In addition, these premature neonates may have increased responsiveness to pain that persists beyond the neonatal period as a result of untreated pain.5 Inadequate sedation can also result in asynchrony with the mechanical ventilator contributing to poor ventilation and ultimately increased NICU length of stay (LOS).2
Fentanyl and morphine are the most commonly used opioids in the NICU,1,2 but there are several advantages of fentanyl compared with morphine in this population. Fentanyl has a shorter duration of action and faster onset than morphine. Its analgesic potency is estimated to be 100 times that of morphine.6,7 Fentanyl is also associated with less hemodynamic 1
University of Missouri Health Care, Columbia, MO, USA University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA 3 University of Oklahoma College of Medicine, Oklahoma City, OK, USA 4 University of Oklahoma College of Public Health, Oklahoma City, OK, USA 2
Corresponding Author: Erin M. Lammers, University of Missouri Health Care, Women’s and Children’s Hospital, 404 N Keene Street, DC546.00, Columbia, MO 65201, USA. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV CALIFORNIA SAN DIEGO on June 11, 2015
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Annals of Pharmacotherapy 48(3)
adverse effects secondary to a lack of histamine release compared with morphine, and it has less effect on gastrointestinal motility.6,7 In neonates, the metabolism of morphine favors the production of the inactive metabolite morphine-3-glucuronide that may antagonize the effects of the parent compound and the active metabolite morphine-6-glucuronide.8 Although the use of opioids for the management of postoperative pain in the neonate is recommended by the American Academy of Pediatrics, data regarding their use for sedation during mechanical ventilation is conflicting.9 In many cases, opioids are delivered via a continuous infusion (CIN) for premature neonates requiring sedation and analgesia while on a mechanical ventilator. Because of their central nervous system activity, opioids may negatively affect the developing brain of a premature neonate. Sedative and analgesic use in a newborn animal model has generated concern that these commonly used medications may cause apoptotic neurodegeneration in neonates.10 Negative short-term effects, including increased mechanical ventilator settings and reduced brain size, as analyzed by magnetic resonance imaging, have been associated with the use of fentanyl CIN in human studies.2,11 Previous studies examining the long-term effects of opioids on neurodevelopment in neonates have focused on the use of morphine CIN.12-14 The long-term neurodevelopmental outcomes of premature neonates exposed to fentanyl in the NICU have not been evaluated. The primary objective of this study was to determine whether there is an association between cumulative fentanyl dose and neurodevelopmental outcome as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) composite scores for language, cognition, or motor skills.
Materials and Methods Study Design This was a retrospective cohort study of very-low-birthweight (VLBW) neonates (ie, ≤1.5 kg) who received follow-up by chronological age of 2 years in the premature infant development clinic between January 2008 to December 2011. Approximately 50% to 60% of VLBW neonates discharged from the institution’s 88-bed level III-C NICU are followed up in this clinic, which equates to approximately 100 to 150 patients per year. Following institutional review board approval, patients were identified within the clinic database. Patients were excluded from the study if they did not have documentedBayley-III scores for language, cognition, and motor skills within the clinic records.15 The Bayley-III is a reliable tool used to assess the neurodevelopment of infants. This tool is considered to have strong reliability coefficients for assessment of language (0.93), cognition (0.91), and motor skills (0.92).15 Additional exclusion criteria related to the hospitalization
included admission to the institution at greater than 24 hours of life, receipt of morphine (ie, scheduled and CIN dosing), grade III or IV IVH, PVL, and fronto-occipital circumference (FOC)
research-article2013
AOPXXX10.1177/1060028013514026Lammers et alLammers et al
Research Report
Association of Fentanyl With Neurodevelopmental Outcomes in Very-Low-Birth-Weight Infants
Annals of Pharmacotherapy 2014, Vol. 48(3) 335–342 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013514026 aop.sagepub.com
Erin M. Lammers, PharmD, BCPS1, Peter N. Johnson, PharmD, BCPS2, Kimberly D. Ernst, MD, MSMI, FAAP3, Tracy M. Hagemann, PharmD, FCCP, FPPAG2, Shelley M. Lawrence, MD, MS3, Patricia K. Williams, MD3, Michael P. Anderson, PhD4, and Jamie L. Miller, PharmD, BCPS2
Abstract Background: Opioids are commonly used in the neonatal intensive care unit (NICU). Negative neurodevelopmental effects in the short-term setting have been associated with opioids ; however, long-term studies have been limited. Objective: The primary objective was to determine if there is a dose relationship between fentanyl and neurodevelopmental outcomes, as measured by Bayley Scales of Infant and Toddler Development (Bayley-III) composite scores for language, cognition, and motor skills. Secondary objectives included comparison of Bayley-III scores and neurodevelopmental impairment classification based on fentanyl exposure. Methods: A retrospective evaluation of 147 very-low-birth-weight infants with Bayley-III scores obtained at a chronological age of 6 months to 2 years at clinic follow-up was conducted. Univariate and multivariable linear regression analyses were used to determine if there was a dose-related association between fentanyl and neurodevelopmental outcomes. To evaluate secondary outcomes, patients were divided based on cumulative fentanyl dose (“high-dose” versus “low/no-dose”). Results: The univariate analysis found a statistically significant decrease in cognition (P = .034) and motor skills scores (P = .006). No association was found in the multi-variable regression between fentanyl cumulative dose and Bayley-III scores. There was a significant decrease in the motor skills score between the high-dose versus low/no-dose group, 94 ± 20 versus 102 ± 15, respectively (P = .026); however, no statistical differences were noted for language or cognition scores or neurological impairment classification. Conclusions: When controlling for other variables, the cumulative fentanyl dose did not correlate with neurodevelopmental outcomes. Further evaluation of benefits and risks of opioids in premature infants are needed. Keywords opioid, fentanyl, midazolam, neurodevelopment, premature, neonate
Introduction Opioid analgesics are commonly used in the neonatal intensive care unit (NICU) for procedural pain, postoperative pain, and sedation with prolonged mechanical ventilation.1,2 A survey of neonatologists revealed that opioids are used to treat pain resulting from medical procedures (eg, central line or chest tube insertion) in more than 90% of patients.3 Untreated pain and agitation in the premature neonate has been associated with negative neurological outcomes, including intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL).4 In addition, these premature neonates may have increased responsiveness to pain that persists beyond the neonatal period as a result of untreated pain.5 Inadequate sedation can also result in asynchrony with the mechanical ventilator contributing to poor ventilation and ultimately increased NICU length of stay (LOS).2
Fentanyl and morphine are the most commonly used opioids in the NICU,1,2 but there are several advantages of fentanyl compared with morphine in this population. Fentanyl has a shorter duration of action and faster onset than morphine. Its analgesic potency is estimated to be 100 times that of morphine.6,7 Fentanyl is also associated with less hemodynamic 1
University of Missouri Health Care, Columbia, MO, USA University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA 3 University of Oklahoma College of Medicine, Oklahoma City, OK, USA 4 University of Oklahoma College of Public Health, Oklahoma City, OK, USA 2
Corresponding Author: Erin M. Lammers, University of Missouri Health Care, Women’s and Children’s Hospital, 404 N Keene Street, DC546.00, Columbia, MO 65201, USA. Email: [email protected]
Downloaded from aop.sagepub.com at UNIV CALIFORNIA SAN DIEGO on June 11, 2015
336
Annals of Pharmacotherapy 48(3)
adverse effects secondary to a lack of histamine release compared with morphine, and it has less effect on gastrointestinal motility.6,7 In neonates, the metabolism of morphine favors the production of the inactive metabolite morphine-3-glucuronide that may antagonize the effects of the parent compound and the active metabolite morphine-6-glucuronide.8 Although the use of opioids for the management of postoperative pain in the neonate is recommended by the American Academy of Pediatrics, data regarding their use for sedation during mechanical ventilation is conflicting.9 In many cases, opioids are delivered via a continuous infusion (CIN) for premature neonates requiring sedation and analgesia while on a mechanical ventilator. Because of their central nervous system activity, opioids may negatively affect the developing brain of a premature neonate. Sedative and analgesic use in a newborn animal model has generated concern that these commonly used medications may cause apoptotic neurodegeneration in neonates.10 Negative short-term effects, including increased mechanical ventilator settings and reduced brain size, as analyzed by magnetic resonance imaging, have been associated with the use of fentanyl CIN in human studies.2,11 Previous studies examining the long-term effects of opioids on neurodevelopment in neonates have focused on the use of morphine CIN.12-14 The long-term neurodevelopmental outcomes of premature neonates exposed to fentanyl in the NICU have not been evaluated. The primary objective of this study was to determine whether there is an association between cumulative fentanyl dose and neurodevelopmental outcome as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) composite scores for language, cognition, or motor skills.
Materials and Methods Study Design This was a retrospective cohort study of very-low-birthweight (VLBW) neonates (ie, ≤1.5 kg) who received follow-up by chronological age of 2 years in the premature infant development clinic between January 2008 to December 2011. Approximately 50% to 60% of VLBW neonates discharged from the institution’s 88-bed level III-C NICU are followed up in this clinic, which equates to approximately 100 to 150 patients per year. Following institutional review board approval, patients were identified within the clinic database. Patients were excluded from the study if they did not have documentedBayley-III scores for language, cognition, and motor skills within the clinic records.15 The Bayley-III is a reliable tool used to assess the neurodevelopment of infants. This tool is considered to have strong reliability coefficients for assessment of language (0.93), cognition (0.91), and motor skills (0.92).15 Additional exclusion criteria related to the hospitalization
included admission to the institution at greater than 24 hours of life, receipt of morphine (ie, scheduled and CIN dosing), grade III or IV IVH, PVL, and fronto-occipital circumference (FOC)
