Editorials
2. Burns ML, Stensvold HJ, Risnes K, et al: on behalf of the Norwegian 4. Wong J, Shah PS, Yoon EW, et al: Inotrope use among extremely
Neonatal Network: Inotropic Therapy in Newborns, A Population-
Based National Registry Study. Pediatr Crit Care Med 2016;
17:948956
3. Giesinger RE, McNamara PJ: Hemodynamic instability in the critically
ill neonate: An approach to cardiovascular support based on disease
pathophysiology. Semin Perinatol 2016; 40:174188
Treatment of Refractory Status Epilepticus in
Children: Current Practice and Opportunities
to Improve Care*
Kimberly Statler Bennett, MD
Division of Critical Care Medicine
Department of Pediatrics
University of Colorado School of Medicine
Aurora, CO
S
tatus epilepticus (SE) is common among critically ill chil-
dren, yet understanding of contemporary care practices
remains incomplete, particularly for refractory SE (RSE).
RSE is commonly defined as continued seizure activity despite
administration of two antiepileptic drugs (AEDs) (1). In this
issue of Pediatric Critical Care Medicine, Tasker et al (2) pro-
vide some welcome insight into treatment patterns for chil-
dren with RSE. Using a multicenter, prospective observational
healthcare delivery database, they characterize the use of IV
infusions of anesthetic agents among 111 children with RSE
treated at nine U.S. pediatric tertiary care hospitals between
2011 and 2013. Their findings provide important information
about contemporary care practices, identify several areas of
deviation from published SE treatment guidelines, and provide
valuable guidance for planning future investigations.
In the study by Tasker et al (2), the choice of treatment for RSE
was left to local care team discretion. RSE may be treated with
intermittently dosed third-line AEDs or with continuous anes-
thetic infusions. Among the 111 children with RSE, 54 (49%) were
treated with anesthetic infusions. Not surprisingly, rates of intu-
bation and vasoactive medication administration were greater
among children receiving anesthetic infusions. Encouragingly,
RSE was terminated by the first cycle of anesthetic infusion in 72%
of episodes. Most children who failed the first cycle responded to a
second cycle, corresponding to termination of RSE in 94% of chil-
dren with one or two cycles of anesthetic infusion. Overall study
*See also p. 968.
Key Words: care delivery; electroencephalographic monitoring;
midazolam; pentobarbital
The author has disclosed that she does not have any potential conflicts
of interest.
Copyright 2016 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000000917
1006 www.pccmjournal.org October 2016 Volume 17 Number 10
Copyright 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
preterm infants in Canadian neonatal intensive care units: Variation
and outcomes. Am J Perinatol 2015; 32:914s
5. Rios DR, Moffett BS, Kaiser JR: Trends in pharmacotherapy for neo-
natal hypotension. J Pediatr 2014; 165:697701.e1
6. Gupta S, Donn SM: Neonatal hypotension: Dopamine or dobuta-
mine? Semin Fetal Neonatal Med 2014; 19:5459
mortality was 3.6% (5.5% for children who received anesthetic
infusions vs. 1.4% for those who did not). Interestingly, a retro-
spective observational study of 151 children with RSE, cared for
at eight PICUs in the United Kingdom from 2008 to 2009, cor-
roborates these rates of anesthetic infusion treatment (50%) and
overall mortality (4%) but reports lower rates of anesthetic infu-
sion efficacy (midazolam, 45%; thiopentone, 40%) (3).
Tasker et al (2) report that midazolam is the most common
agent for initial anesthetic infusion treatment, which concurs
with contemporary SE treatment guidelines (4). Midazolam
was administered to 78% (42/54) of children and achieved sei-
zure control in 71% (30/42). Efficacious dosing of midazolam
rarely reached truly anesthetic levels. The median infusion
duration was 47.5 hours for responders, compared with 24
hours for nonresponders. Pentobarbital was the most com-
mon agent for second-cycle anesthetic infusion. Twelve chil-
dren received pentobarbital; 11 of whom had failed midazolam
infusion. Pentobarbital terminated RSE in 75% (9/12). For
responders, the median infusion duration was 3 days. Account-
ing for both midazolam and pentobarbital treatment, the total
median anesthetic infusion duration was 4 days.
Hemodynamic effects were not uncommon. Vasopressor
medications were administered to 29% (12/42) of children
managed with midazolam (2). This is greater than the rate of
2.3% reported in a recent systematic review of pediatric RSE
treatment (5). However, 58% (7/12) of treated children also
received pentobarbital, and it is unclear from the text whether
vasoactive medications were required during midazolam, pen-
tobarbital, or both. In contrast, vasoactive medications were
administered to 64% (7/11) of children treated with pentobar-
bital (2), which is compared with rates of 93100% in prior
reports (5). These data emphasize the importance of anticipat-
ing and proactively preventing hemodynamic complications
during anesthetic infusion treatment for RSE.
Tasker et al (2) report a median time from seizure onset to
first-cycle anesthetic infusion initiation of 145 minutes. In con-
trast, contemporary SE treatment guidelines (35) advocate
that for RSE escalation to third-line AEDs, including anesthetic
infusions, be accomplished within 2070 minutes of SE onset.
Time from SE onset to first, second, and third AED dosing has
been shown to positively correlate with the duration of RSE (6),
and aggressive care has been associated with both shorter SE

duration and improved outcomes (7). As Tasker et al (2) dis-
cuss, such knowledge has prompted efforts to shorten time to
initial AED administration and speed escalation between AED
types. However, less attention has been focused on shortening
times to initiation of anesthetic infusions or assuring timely
reassessment or steady escalation of anesthetic infusion therapy.
Refinements to anesthetic infusion management will likely
prove important for improved RSE treatment. For example,
application of high-dose midazolam infusion algorithms,
which incorporate frequent, scheduled reassessments and
robust dose increases, suggests that more aggressive uptitration
of medication dosing may lead to more rapid RSE termination
(5, 8). In addition, Tasker et al (2) report a median duration
of midazolam infusion in nonresponders of 24 hours. More
timely recognition and quicker response to anesthetic infusion
treatment failures may be possible. Further characterization
of current care delivery variability and identification of barri-
ers to timely initiation and adjustment of anesthetic infusion
therapy in children with RSE are warranted.
Therapeutic endpoints for anesthetic infusion treatment
include cessation of clinical seizures, cessation of electroen-
cephalographic seizures, and burst suppression. Controversy
persists regarding the most optimal endpoint, but contempo-
rary SE treatment guidelines advocate electroencephalographic
guidance (4). In the study by Tasker et al (2), selection of treat-
ment endpoint remained at the discretion of local care teams.
Surprisingly, an endpoint of clinical seizure termination was
chosen in 48% of children during the first cycle of anesthetic
infusion and in 25% of patients during the second cycle. As
discussed in a prior report (5), clinical (vs electroencephalog-
raphy) endpoints have been associated with lower medication
dosing and more rapid achievement of therapeutic goals (e.g.,
clinical seizure control). However, targeting a clinical endpoint
may undertreat nonconvulsive seizures and nonconvulsive SE
(NCSE). Continuous electroencephalographic monitoring of
117 critically ill children with SE or unexplained alterations
in consciousness revealed nonconvulsive seizures in 39% and
NCSE in 23% (9). Occurrence of in-hospital seizures increased
the odds for nonconvulsive seizures by 14.8-fold for children
younger than 2 years old and 8.9-fold for those 2 years old or
older. Recognition of electroencephalographic utility to detect
Pediatric Critical Care Medicine www.pccmjournal.org 1007
Copyright 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
Editorials
nonconvulsive seizures and NCSE among pediatric SE patients
is growing; however, ongoing advocacy is needed to promote
wider adoption of this practice. Similarly, additional investi-
gations are needed to help clarify optimal electroencephalo-
graphic endpoints (seizure cessation vs burst suppression)
during anesthetic infusion therapy of RSE in children.
In summary, Tasker et al (2) provide needed insight into
current care practices for pediatric RSE. Their findings once
again demonstrate the benefits of multicenter collaborations
to better understand current treatment practices and identify
potential areas for refinement. Finally, their work should help
inform the design of both local quality improvement initiatives
and future clinical investigations. Such efforts will prove essen-
tial to improving the care and outcomes of children with SE.
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