Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital. (Emrath)

Tasker RC, et al. Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital. Pediatr Crit Care Med. 2016 Oct;17(10):968-975.

OBJECTIVE: To describe pediatric patients with convulsive refractory status epilepticus in whom there is intention to use an IV anesthetic for seizure control.

DESIGN: Two-year prospective observational study evaluating patients (age range, 1 mo to 21 yr) with refractory status epilepticus not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent.

SETTING: Nine pediatric hospitals in the United States.

PATIENTS: In a cohort of 111 patients with refractory status epilepticus (median age, 3.7 yr; 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment.

MAIN RESULTS: The median (interquartile range) ICU length of stay was 10 (3-20) days. Up to four “cycles” of serial anesthetic therapy were used, and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9-34) hours for the first cycle and longer when a second cycle was required (30 [4-120] hr; p = 0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam nonresponders, transition to a second agent occurred after a median of 1 day. Most patients (94%) experienced seizure termination with these two therapies.

CONCLUSIONS: Midazolam and pentobarbital remain the mainstay of continuous infusion therapy for refractory status epilepticus in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study.

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Fentanyl and Midazolam Are Ineffective in Reducing Episodic Intracranial Hypertension in Severe Pediatric Traumatic Brain Injury.

Welch TP, et al. Fentanyl and Midazolam Are Ineffective in Reducing Episodic Intracranial Hypertension in Severe Pediatric Traumatic Brain Injury. Crit Care Med. 2016 Apr;44(4):809-18.

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.

Dexmedetomidine use in the ICU: Are we there yet? (Pham)

Ahmed S, Murugan R. Dexmedetomidine use in the ICU: Are we there yet? Crit Care. 2013 May 31;17(3):320.

BACKGROUND: Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha-2 agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.

METHODS: OBJECTIVE: The objective was to determine the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation, and improving patients’ interaction with nursing care.

DESIGN: Two phase 3 multicenter, randomized, double-blind trials were conducted.

SETTING: The MIDEX (Midazolam vs. Dexmedetomidine) trial compared midazolam with dexmedetomidine in ICUs of 44 centers in nine European countries. The PRODEX (Propofol vs. Dexmedetomidine) trial compared propofol with dexmedetomidine in 31 centers in six European countries and two centers in Russia.

SUBJECTS: The subjects were adult ICU patients who were receiving mechanical ventilation and who needed light to moderate sedation for more than 24 hours.

INTERVENTION: After enrollment, 251 and 249 subjects were randomly assigned midazolam and dexmedetomidine, respectively, in the MIDEX trial, and 247 and 251 subjects were randomly assigned propofol and dexmedetomidine, respectively, in the PRODEX trial. Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials were employed.

OUTCOMES: For each trial, investigators tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were the ability of the patient to communicate pain (measured by using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol (midazolam, n = 233, versus dexmedetomidine, n = 227; propofol, n = 214, versus dexmedetomidine, n = 223) population.

RESULTS: Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% confidence interval (CI) 0.97 to 1.18), and dexmedetomidine/propofol ratio in time at target sedation was 1.00 (95% CI 0.92 to 1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours, interquartile range (IQR) 67 to 337) versus midazolam (164 hours, IQR 92 to 380; P = 0.03) but not with dexmedetomidine (97 hours, IQR 45 to 257) versus propofol (118 hours, IQR 48 to 327; P = 0.24). Patient interaction (measured by using VAS) was improved with dexmedetomidine (estimated score difference versus midazolam 19.7, 95% CI 15.2 to 24.2; P <0.001; and versus propofol 11.2, 95% CI 6.4 to 15.9; P <0.001). Lengths of ICU and hospital stays and mortality rates were similar. Dexmedetomidine versus midazolam patients had more hypotension (51/247 [20.6%] versus 29/250 [11.6%]; P = 0.007) and bradycardia (35/247 [14.2%] versus 13/250 [5.2%]; P <0.001).

CONCLUSIONS: Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved the ability of patients to communicate pain compared with midazolam and propofol. Greater numbers of adverse effects were associated with dexmedetomidine.

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Comparison of low-dose ketamine to midazolam for sedation during pediatric urodynamic study. (Pham)

Paediatr Anaesth. 2013 May;23(5):415-21. PMID: 23061785

INTRODUCTION: Aim of sedation during pediatric urodynamic studies (UDS) is a calm and cooperative child while not affecting measurements. We compared the effectiveness of midazolam to low-dose ketamine infusion for sedation and their impact on urodynamics.

MATERIALS AND METHODS: ASA-I children undergoing UDS were randomly assigned to group K (ketamine) loading dose (0.25 mg·kg(-1) ) followed by infusion of 10-20 μg·kg(-1) ·min(-1) or group M (midazolam) loading dose of (0.02 mg·kg(-1) ) followed by 1-2 μg·kg(-1) ·min(-1) . The sedation scores and reactivity to catheterization were monitored by Children Hospital of Wisconsin Sedation Scale and Frankl Behavior Rating Scale, respectively. The UDS included two-channel filling cystometry in supine position followed by a free uroflowmetry in sitting position. The UDS was performed and interpreted in accordance with good urodynamic practice guidelines of International Continence Society (2002).

RESULTS: A total of 34 children were enrolled. Group K children (n = 17) attained sedation earlier 6.80 (±3.36) min vs. 9.40 (±2.82) min; (P = 0.03) than group M (n = 17) and also recovered earlier 11.60 (±3.13) min vs. 19.67 (±5.49) min (P = 0.01). Reactivity scores during urinary and rectal catheterization were lower in group K (P = 0.03 and 0.01), respectively. Historical UDS data of 21 participants were available for comparison with effect of medication. None of the study drugs affected UDS parameters significantly.

CONCLUSIONS: Midazolam or low-dose ketamine provide satisfactory sedation during pediatric UDS without impacting urodynamic values.

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