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 (ICH) in children with severe traumatic brain injury (TBI). Design Retrospective cohort. Setting Pediatric intensive care unit (PICU) in a university-affiliated children’s hospital Level I trauma center. Patients Thirty-one children aged 0–18 years with severe TBI (Glasgow Coma Scale Score ≤ 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic ICH. Interventions None. Measurements and Main Results The area under the curve (AUC) from high resolution intracranial pressure (ICP) pressure-time plots was calculated to represent cumulative ICH exposure: AUC for ICP above 20 mmHg (AUC-ICH) was calculated in 15 minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic ICH. Our primary outcome measure, the difference between pre- and post-drug administration epochs (ΔAUC-ICH), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism and time after injury; time after injury correlated with ΔAUC-ICH. 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, ICH rose after administration of fentanyl and/or midazolam (overall aggregate mean ΔAUC-ICH= +17 mmHg*min, 95%CI 0–34 mmHg*min; p=0.04). The mean ΔAUC-ICH 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 ΔAUC-CPP). Conclusions Bolus dosing of fentanyl and midazolam fails to reduce the ICH burden when administered for episodic ICH. Paradoxically, we observed an overall increase in ICH 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.

Analgesia, Sedation, and Intracranial Pressure

“…In this issue of the Journal , Welch et al (1) present a work that comes in the tradition started by Nils Lundberg in 1960 (2) and latterly exemplified by so-called “multimodality monitoring in neurocritical care” (3). Lundberg's thesis demonstrated that continuous monitoring of cerebral ventricular fluid pressure and inspection of graphic recordings of pressure variations over time “give information of practical diagnostic significance” (2).…”

“…Welch et al (1) describe time-series analyses and findings from a retrospective study into the effect of doses of sedatives and analgesics on ICP and cerebral perfusion pressure (CPP, the difference between mean blood pressure and mean ICP) in pediatric patients after severe TBI. The authors found that bolus dosing of midazolam and fentanyl were ineffective at treating episodic intracranial hypertension.…”

“…This finding will come as no surprise to practitioners who care for adult patients after severe TBI, since lack of effect is well described in that population (5-10). One key issue, however, that makes this new report (1) noteworthy is that in contrast to adult practice – in which standard sedation is a combination of propofol and midazolam, with morphine, fentanyl and alfentanil/sufentanil as the main analgesics (11) – propofol is not available for continuous infusion in the pediatric intensive care unit (12). Readers may wonder whether, given these data, our sedation and analgesia strategy should now change.…”

“…Readers may wonder whether, given these data, our sedation and analgesia strategy should now change. We should therefore focus on the why, what and when of bolus dosing of sedatives and analgesics in pediatric patients after severe TBI and explore in more detail the clinical context of the cases studied by Welch et al (1). …”

“…Additional bolus doses may be given in anticipation of a procedure, or in response to an obvious change in state with agitation, anxiety or pain. In the series reported by Welch et al (1) there were 31 patients with 413 episodes of ICP >20 mm Hg lasting at least 5 minutes and, of these, 211 episodes were treated with a bolus dose of midazolam and/or fentanyl. The authors do not know why ICP was raised during these episodes, but simply that bedside attendants chose to administer either midazolam (high-dose >0.1 mg/kg or low-dose ≤0.1 mg/kg) and/or fentanyl (high-dose >1 μg/kg or low-dose ≤1 μg/kg) as immediate treatment.…”