title: Fentanyl and Midazolam Are Ineffective in Reducing Episodic Intracranial Hypertension in Severe Pediatric Traumatic Brain Injury.
abstract: OBJECTIVE
  To evaluate the clinical effectiveness of bolus-dose fentanyl and midazolam to treat episodic intracranial hypertension in children with severe traumatic brain injury.
  
  
  METHODS
  Retrospective cohort.
  
  
  METHODS
  PICU in a university-affiliated children's hospital level I trauma center.
  
  
  METHODS
  Thirty-one children 0-18 years of age with severe traumatic brain injury (Glasgow Coma Scale score of ≤ 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic intracranial hypertension.
  
  
  METHODS
  None.
  
  
  RESULTS
  The area under the curve from high-resolution intracranial pressure-time plots was calculated to represent cumulative intracranial hypertension exposure: area under the curve for intracranial pressure above 20 mm Hg (area under the curve-intracranial hypertension) was calculated in 15-minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic intracranial hypertension. Our primary outcome measure, the difference between predrug and postdrug administration epochs (Δarea under the curve-intracranial hypertension), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism, and time after injury; time after injury correlated with Δarea under the curve-intracranial hypertension. In a mixed-effects model, with patient as a random effect, drug/dose combination as a fixed effect, and time after injury as a covariate, intracranial hypertension increased after administration of fentanyl and/or midazolam (overall aggregate mean Δarea under the curve-intracranial hypertension = +17 mm Hg × min, 95% CI, 0-34 mm Hg × min; p = 0.04). The mean Δarea under the curve-intracranial hypertension increased significantly after administration of high-dose fentanyl (p = 0.02), low-dose midazolam (p = 0.006), and high-dose fentanyl plus low-dose midazolam (0.007). Secondary analysis using age-dependent thresholds showed no significant impact on cerebral perfusion pressure deficit (mean Δarea under the curve-cerebral perfusion pressure).
  
  
  CONCLUSIONS
  Bolus dosing of fentanyl and midazolam fails to reduce the intracranial hypertension burden when administered for episodic intracranial hypertension. Paradoxically, we observed an overall increase in intracranial hypertension burden following drug administration, even after accounting for within-subject effects and time after injury. Future work is needed to confirm these findings in a prospective study design.
authors.affiliation: 1Division of Critical Care Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO. 2Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO. 3Division of Biostatistics, Washington University School of Medicine, St. Louis, MO. 4Department of Neurosurgery, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Welch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wallendorf
authors.forename: Evan D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Leonard
authors.forename: Allan
authors.initials: A
authors.lastname: Doctor
authors.forename: Jose A
authors.initials: JA
authors.lastname: Pineda
mesh_terms: D000293:Adolescent; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D002560:Cerebrovascular Circulation / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005283:Fentanyl / Q000627:therapeutic use*; D015600:Glasgow Coma Scale; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D007223:Infant; D007231:Infant, Newborn; D019586:Intracranial Hypertension / Q000188:drug therapy* / Q000209:etiology; D007427:Intracranial Pressure / Q000502:physiology; D008297:Male; D008874:Midazolam / Q000627:therapeutic use*; D012189:Retrospective Studies; D017211:Treatment Failure
chemical_list: D006993:Hypnotics and Sedatives; D008874:Midazolam; D005283:Fentanyl