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.

Design: Retrospective cohort.

Setting: PICU in a university-affiliated children's hospital level I trauma center.

Patients: 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.

Interventions: None.

Measurements and main 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.

Figure 1

Patient flow diagram; TBI, traumatic brain injury; GCS, Glasgow Coma Scale; ICP, intracranial pressure; ICH, intracranial hypertension

Figure 2

a. Example of a high-resolution tracing from a representative patient showing non-favorable response to treatment. Time axis represents a 30-minute recording interval, with equal 15-minute epochs before and after drug administration. Patient met criteria at 5:50. This patient was a 16-year-old male who suffered a gunshot wound, and presented with GCS 5. Fentanyl 2 mcg/kg and Midazolam 0.04 mg/kg (FH/ML) were given at time 06:00, denoted by the vertical arrow. Age-based CPP threshold was 60 mmHg. b. Example of a high-resolution tracing from representative a patient showing favorable response to treatment. Time axis represents a 30-minute recording interval, with equal 15-minute epochs before and after drug administration. Patient met criteria at 4:57. This patient was a 3-month-old male who suffered a non-accidental trauma, and presented with GCS 6. Fentanyl 1 mcg/kg and Midazolam 0.1 mg/kg (FL/ML) were given at time 05:07, denoted by the vertical arrow. Age-based CPP threshold was 45 mmHg.

Figure 2

a. Example of a high-resolution tracing from a representative patient showing non-favorable response to treatment. Time axis represents a 30-minute recording interval, with equal 15-minute epochs before and after drug administration. Patient met criteria at 5:50. This patient was a 16-year-old male who suffered a gunshot wound, and presented with GCS 5. Fentanyl 2 mcg/kg and Midazolam 0.04 mg/kg (FH/ML) were given at time 06:00, denoted by the vertical arrow. Age-based CPP threshold was 60 mmHg. b. Example of a high-resolution tracing from representative a patient showing favorable response to treatment. Time axis represents a 30-minute recording interval, with equal 15-minute epochs before and after drug administration. Patient met criteria at 4:57. This patient was a 3-month-old male who suffered a non-accidental trauma, and presented with GCS 6. Fentanyl 1 mcg/kg and Midazolam 0.1 mg/kg (FL/ML) were given at time 05:07, denoted by the vertical arrow. Age-based CPP threshold was 45 mmHg.

Figure 3

ΔAUC-ICH mixed model with subject as random effect and drug class as fixed effect. Drug classes represent each dose class contrasted with situation of no drug. Analyses are controlled for time after injury. Data represent least squares mean ΔAUC-ICH with upper and lower confidence bounds, * represents significance at p <0.05. For fentanyl doses; FH: >1 mcg/kg, FL: <1 mcg/kg, F0: none. For midazolam doses; MH: >0.1 mg/kg, ML: <0.1 mg/kg, M0: none. No data points for dose F0/MH (all instances of this drug class were excluded because time after injury data was not available for those patients).

Figure 4

ΔAUC-CPP mixed model with subject as random effect and drug class as fixed effect. Drug classes represent each dose class contrasted with situation of no drug. Analyses are controlled for post-resuscitation GCS. Data represent least squares mean ΔAUC-CPP with upper and lower confidence bounds. No drug class was significant at p< 0.05. For fentanyl doses; FH: >1 mcg/kg, FL: <1 mcg/kg, F0: none. For midazolam doses; MH: >0.1 mg/kg, ML: <0.1 mg/kg, M0: none.

Figure 5

Median PILOT scores by day of therapy. Data represents median, interquartile range (IQR), and distribution of raw data points. Only one patient was receiving study drugs on day 5.