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1 ScienceDirect 66
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4 Biomedical Journal 69
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6 journal homepage: www.elsevier.com/locate/bj
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9 Original Article 75
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Therapeutic hypothermia for pediatric refractory 77
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status epilepticus May Ameliorate post-status 79
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16 Q9 epilepticus epilepsy 81
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19 Q8 Mei-Hsin Hsu b,1, Hsuan-Chang Kuo b,d,1, Jainn-Jim Lin c, Ming-Yi Chou a, 85
20 Ying-Jui Lin b,**,1, Pi-Lien Hung a,*,1 86
21 87
22 a
Division of Pediatric Neurology, Department of Pediatrics at Kaohsiung Chang Gung Memorial Hospital, Chang 88
23 Gung University College of Medicine, Kaohsiung, Taiwan 89
24 b
Division of Pediatric Critical Care, Department of Pediatrics at Kaohsiung Chang Gung Memorial Hospital, Chang 90
25 Gung University College of Medicine, Kaohsiung, Taiwan 91
26 c
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Division of Pediatric Critical Care and Emergency Medicine, Chang Gung Children's Hospital and Chang Gung
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Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
28 d 94
Department of Nursing, Meiho University, Taiwan
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30 96
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32 article info abstract
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33 99
34 Article history: Background: To compare the clinical characteristics and outcomes of pediatric patients with
100
35 Received 5 November 2019 refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) who
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36 Received in revised form received therapeutic hypothermia (TH) plus anticonvulsants or anticonvulsants alone. 102
37 23 March 2020 Material and methods: Two-medical referral centers, retrospective cohort study. 103
38 Accepted 17 April 2020 Setting: Pediatric Intensive Care Unit (PICU) at Taoyuan Chang Gung Children's hospital and 104
39 Available online xxx Kaohsiung Chang Gung Memorial Hospital. 105
40 106
Patients: We reviewed the medical records of 23 patients with RSE/SRSE who were admitted
41 107
Keywords: to PICU from January 2014 to December 2017. Of these, 11 patients received TH (TH group)
42 108
Therapeutic hypothermia and 12 patients did not (control group).
43 109
44 Pediatric refractory status epilepticus Results: The selective endpoints were RSE/SRSE duration, length of PICU stay, and Glasgow
110
45 Pharmacoresistant refractory status Outcome Scale (GOS) score. We applied TH using the Artic Sun® temperature management
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46 epilepticus system (target temperature, 34e35
C; duration, 48e72 h). Of the 11 patients who received
112
47 Post-status epilepticus epilepsy TH, 7 had febrile infection-related epilepsy syndrome (FIRSE), one had Dravet syndrome,
113
48 Febrile infection-related epilepsy syn- and three had traumatic brain injury. The TH group had significantly shortern seizure 114
49 drome durations than did the control group (hrs; median (IQR) 24(40) vs. 96(90), p < 0.05). Two 115
50 Temperature management system patients in the TH group died of pulmonary embolism and extreme brain edema. The 116
51 length of PICU stay was similar between the groups (days; median (IQR) 30(42) v.s 117
52 118
30.5(30.25)). The TH group had significantly better long-term outcomes than did the control
53 119
group (GOS score, median (IQR) 4(2) v.s 3 (0.75), p ¼ 0.01*). The TH group had a significantly
54 120
55 121
56 * Corresponding author. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of 122
57 Medicine, No. 123 Ta-Pei Rd., Niao-Song District, Kaohsiung, Taiwan. 123
58 ** Corresponding author. Q1 124
59 E-mail address: flora1402@cgmh.org.tw (P.-L. Hung). 125
60 Peer review under responsibility of Chang Gung University. 126
61 1
Mei-Hsin Hsu and Hsuan-Chang Kuo contributed equally to the paper. Ying-Jui Lin and Pi-Lien Hung contributed equally to advising 127
62 the manuscript. 128
63 https://doi.org/10.1016/j.bj.2020.04.004 129
64 2319-4170/© 2020 Chang Gung University. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004
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1 lower incidence of later chronic refractory epilepsy than did the control group (TH v.s non- 66
2 TH, 5/11 (45%) v.s. 12/12(100%), p < 0.01). 67
3 Conclusions: TH effectively reduced the seizure burden in patients with RSE/SRSE. Our 68
4 findings support that for patients with RSE/SRSE, TH shortens the seizure duration, ulti- 69
5 mately reducing the occurrence of post-status epilepticus epilepsy and improving patients’ 70
6 long-term survival.
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12 Q2 Status epilepticus (SE) is defined as convulsions persisting for 2014 and December 2017. Taoyuan Chang Gung Children's 77
13 >5 min [1e3]. The gold standard treatment for SE is anti- hospital and Kaohsiung Chang Gung Memorial Hospital are 78
14 epileptic drugs (AEDs). However, up to 44% of SE cases two of the largest tertiary referral centers in northern and 79
15 cannot be controlled by first-line agents, with many such southern Taiwan, and each contains 20 beds for children 80
16 cases exhibiting refractory status epilepticus (RSE) [4]. Re- with critical medical conditions. The study was approved by 81
17 82
fractory status epilepticus is defined as clinical or electroen- the institutional review board of the Chang Gung Memorial
18 83
cephalographic seizures lasting >60 min despite treated with Hospital.
19 84
20 at least one first-line AED (e.g., benzodiazepine) and one The enrolled patients were aged between 1 week and 17 85
21 second-line AEDs (e.g., phenytoin, phenobarbital, or val- years. All patients with clinical or electroencephalographic 86
22 proate) [2,5,6]. Super-refractory status epilepticus (SRSE) is seizures lasting >60 min despite being treated with at least 87
23 defined as SE that has persisted or recurred for 24 h after the one first-line or second-line AED (e.g., benzodiazepine) and 88
24 onset of general anesthesia treatment [7]. Both RSE and SRSE one second-line AED were diagnosed with RSE. Patients 89
25 are considered neurologic emergencies, because the patient encountered status epileptics that has persisted or 90
26 can develop complications including hypoglycemia, brain recurred for 24 h after the onset of being treatedwith 91
27 injury, rhabdomyolysis, related kidney injury, prolonged general anesthesia were diagnosed as SRSE [2,5,6]. The 92
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intensive care unit (ICU), hospital stays, and even death [4,8]. patients with RSE/SRSE were divided into the TH group
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The current treatment option for RSE/SRSE is to use contin- (received anticonvulsants and TH to control seizures) or
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uous anestheticagents, such as propofol, midazolam, barbi- the control group (received only anticonvulsants to control
31 96
32 turate, or ketamine, until a burst-suppression pattern is seizures). Patients who had contraindications for TH (e.g., 97
33 observed during electroencephalography [2,3,5,9,10]. Unfor- coagulopathy) or economic concerns were categorized into 98
34 tunately, these medications only achieve this effect in 64e78% the control group. 99
35 of patients [10]. Thus, alternative therapeutic approaches with We collected the demographic and clinical data of the pa- 100
36 better efficacies are needed for patients with RSE/SRSE. tients in both groups, including age, sex, length of PICU stay, 101
37 One such approach that has been used as a complemen- RSE/SRSE duration, AEDs regimens, 1- year outcome, as 102
38 tary treatment in RSE is therapeutic hypothermia (TH) measured with the Glasgow Outcome Scale (GOS) and Post- 103
39 [2,5,8,11]. The use of TH dates back to early as 400BC when Status Epilepticus Epilepsy 1 year later. The GOS scores were 104
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Hippocrates used snow and ice to reduce hemorrhage [5]. classified as grade 1, dead; grade 2, vegetative state; grade
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Moreover, Britton published a medical report on the use of TH 3,severely disabled; grade 4, moderately disabled; grade 5,
42 107
43 in 1930. Since then, TH has been utilized in variable conditions good (no remained neurological sequelae). 108
44 to protect neurons and improve outcomes. A variety of studies 109
45 have been published demonstrating the effects of TH in open- Therapeutic hypothermia 110
46 heart surgery [12e14], cardiac arrest [15,16], neonatal hypoxic 111
47 ischemic encephalopathy [17e19], and traumatic brain injury We introduced TH as an adjunctive treatment for RSE/SRSE by 112
48 [20]. However, studies employing TH for seizure control are using the Artic Sun® temperature management system with 113
49 still limited, and the results are diverse, especially in pediatric Artic Gel™ pads (Medivance, Inc. of Louisville, Colo- 114
50 groups [2,21]. Therefore, the aim of the present study was to rado,U.S.A.). The pads feature a thin hydrogel coating that 115
51 116
compare the short-term and long-term outcomes between ensures they maintain contact with the patient's skin
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patients with RSE who did and did not receive TH. throughout the treatment.
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The TH protocol is shown in Fig. 1. Hemodynamic moni-
54 119
55 toring with arterial pressure measurement and Patient 120
56 Monitor (IntelliVue MP 60,Philips Monitor) were set up before 121
57 Material and methods TH. Midazolam continuous infusion and Rocuronium contin- 122
58 uous infusion for sedation and anti-shivering were also 123
59 Patient population administered before TH. In our TH cooling protocol for SE, the 124
60 target temperature was set at 34e35
C and the cooling period 125
61 We reviewed the medical records of all patients with RSE/ was 48e72 h. For rewarming, the temperature was increased 126
62 SRSE who were admitted to the Pediatric Intensive Care Unit by 0.05
per hour. The rewarming period was 1e2 days or until 127
63 128
(PICU) of the Department of Pediatrics at two medical referral the body temperature reached 36
C. Following this, normo-
64 129
centers, Taoyuan Chang Gung Children's hospital and thermia (36
C) was maintained for 1e2 days. We recorded all
65 130
Kaohsiung Chang Gung Memorial Hospital, between January of the complications that occurred during TH, including

Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004
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1 66
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This protocol applies for patients with status epilepticus or suspection of acute encephalitis / encephalopathy
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4 1. Admission to PICU with intensive critical care 69
5 70
6 2. Assure the patient has the following supportive equipment before hypothermia therapy: 71
7 a. Endotracheal intubation (RSI, Rapid Sequence Intubation ) with artificial ventilation to keep PCO2 at 35 to 72
8 73
9 40 mmHg (do not over-ventilate). 74
10 75
b. If possible, set up arterial catheter to monitor arterial pressure
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12 c. If possible, set up CVP catheter to assess fluid volume. Goal CVP 6-10 mmHg 77
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3.
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15 a. Obtain continuous core temperature via esophageal probe 80
16 81
17 b. Assess baseline 12 Lead EKG 82
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c. Check ABG, CBC/DC, PT/APTT, Fibrinogen, D-Dimer, BUN/Cr, Na/K/Ca/Cl/P/Mg, AST, Bil (T/D),
19 84
20 albumin, CRP, lactate, amylase, lipase, cardiac enzyme, CPK isoenzyme 85
21 86
4. Sedate patient with midazolam continuous infusion [2-20mcg/kg/min] and anti-shivering drug as Rocuronium
22 87
23 [6-12mcg/kg/min]. 88
24 89
25 5. Intracranial pressure is controlled by the followings: 90
26 a. Fluid infusion between 80 and 100 ml/kg/day. Fluid control must not be reduced more than necessary in
91
27 92
28 order to maintain blood pressure and cerebral circulation. 93
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b. Maintain head of bed at 30 degrees.
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31 c. Submitted hypertonic 3% NaCl 96
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33 6. Steroid pulse therapy: methylprednisolone 30 mg/kg over three hours for three days 98
34 7. Administer esomeprazole or other PPI drugs to prevent stress ulcer. 99
35 100
36 8. Cooling phase: 101
37 102
a. Brain hypothermia therapy uses Arctic Sun cooling system, to induce target body temperature (direct
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39 esophageal temperature 34.0 to 35.0 degrees) within three hours of onset. 104
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41 b. Anti-seizure medication: midazolam, 2 to 20 mcg/kg/min or Thiamylal Sodium, 2-5 mg/kg/hr. 106
42 c. Sedation depth should be confirmed by portable electroencephalograph (Nicolet) as reaching suppression 107
43 108
44 burst within six hours of beginning therapy. 109
45 110
9. Cooling period:
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47 a. Target temperature to be maintained for 48 hours (or maximum 72 hours). 112
48 113
b. Patients achieving a positive sedation depth should reduce the anti-seizure medication dose prior to
49 114
50 rewarming 115
51 116
52 c. [Caution] If spikes remain with suppression bursts, consider complete suppression 117
53 118
d. Manage electrolyte abnormalities and blood glucose.
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55 e. Administer antibiotics appropriate. 120
56 121
10. Rewarming period
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58 a. Rewarming is implemented at a pace of 0.05 degrees per hour. 123
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60 b. When the body temperature backs up to 36.0 degrees, we will keep body temperature at 36.0 degrees for 24 125
61 hours to prevent rebounding IICP. 126
62 127
63 Fig. 1 Our protocol of therapeutic hypothermia therapy for patients with status epileptics or suspection of acute encephalitis/ 128
64 encephalopathy. 129
65 130

Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004
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28 Fig. 2 Boxplot for comparing the two groups of the RSE duration. We found the TH group had significantly shorter RSE duration 93
29 than control group. 94
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31 96
32 97
33 98
34 electrolyte imbalances, arrhythmia, infection, and coagulop- 99
35 Q3 athy, among others (see Fig. 2). Results 100
36 101
37 Case descriptions of patients in the TH group 102
38 Statistical analysis 103
39 During the study period, 11 patients with RSE/SRSE received 104
40 TH with the Artic Sun® temperature management system, 105
The age, sex, RSE/SRSE duration, length of PICU stay, AED
41 and these patients were categorized into the TH group. The 106
regimen, and GOS score of patients with RSE/SRSE from the
42 107
two clinical groups were compared using the ManneWhitney demographic and clinical characteristics of these patients are
43 108
U test was utilized for the age comparisons, RSE/SRSE dura- listed in Table 1. 7 patients (A, B, G, H, I, J, K) had an underlying
44 109
45 tion and length of PICU stay. In addition, the chi-square test or etiology of newly diagnosed FIRES, suffered from relatively 110
46 Fisher's exact test was applied for categorical variables anal- long SE durations (48 and 96 h, respectively), and exhibited 111
47 ysis. Statistical testing was performed using the SPSS software poor responses to multipleAEDs. The SE of these patients was 112
48 (version 18; _SPSS Inc., Chicago, Ill., USA). Differences were finally controlled (achieved a burst-suppression pattern) with 113
49 considered significant at a p-value 0.05. continuous thiamydial infusions and propoful infusions plus 114
50 115
51 116
52 117
53 Table 1 Clinical information of patients underwent therapeutic hypothermia. 118
54 Age at onset/Sex Etiology for SE TH Target temp (
C) TH Duration (hrs) Complications of TH 119
55 120
56 Patient A 13yo/M FIRES 35 72 Electrolyte imbalance, Bradycardia 121
Patient B 13yo/M FIRES 34.5 72 Bradycardia, Infection
57 122
Patient C 8yo/M Dravet syndrome 35 48 Electrolyte imbalance, Infection
58 123
Patient D 8 mo/M TBI post minor neurosurgery 34 72 Electrolyte imbalance
59 124
Patient E 6 mo/M TBI post minor neurosurgery 34 72 Electrolye imbalance, Coagulopathy
60 125
Patient F 2 mo/M TBI post minor neurosurgery 35 48 Electrolye imbalance, Coagulopathy
61 126
Patient G 8yo/M FIRES 34 120 Electrolye imbalance
62 Patient H 4yo/M FIRES 35 72 Electrolye imbalance
127
63 Patient I 6yo/F FIRES 35 48 Electrolye imbalance 128
64 Patient J 6yo/F FIRES 35 48 Electrolye imbalance 129
65 Patient K 10yo/M FIRES 33 120 Electrolye imbalance, Tachycardia 130

Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004
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1 TH. These patients also had relatively long PICU stays. Un- regimen used were identified between the groups, indicating 66
2 fortunately, Patient B suddenly passed away due to pulmo- that the baseline conditions of the two groups were similar. 67
3 nary embolism while recovering from FIRES. However, the 68
4 complication was related to prolonged immobility in the PICU, RSE/SRSE duration 69
5 70
not to TH.Patient C (an 8-year-old boy) had an underlying The seizure durations ranged from 3 to 96 h in the TH group
6 71
disease of Dravet syndrome, which was genetically proven to and from 6 to 192 h in the control group. The seizure duration
7 72
be related to an SCN1A mutation. He developed refractory SE was significantly shorter in the TH group than it was in the
8 73
9 due to an influenza infection. Poor responsiveness to AEDs control group (hrs; median (IQR) 24(40) vs. 96(90), p < 0.05). 74
10 was observed due to persistent high fever. We applied TH 75
11 along with continuous midazolam infusions. Soon after, burst Length of PICU stay 76
12 suppression was achieved. The patient recovered well after The PICU stay in the TH group ranged from 8 to 83 days, while 77
13 rewarming, without cognition or motor function that in the control group ranged from 4 to 58 days. No differ- 78
14 deteriorations. ence in the length of PICU stay was identified between the TH 79
15 Patient D (8-month-old boy) had a traumatic brain injury and control groups (days; median (IQR) 30(42) v.s 30.5(30.25)). 80
16 owing to a car accident. He underwent subdural hematoma 81
17 82
decompression immediately after arrival. However, his SE GOS score
18 83
continued, despite the administration of multiple AEDs. The 3 of the 11 patients (27.2%) in the TH group had an excellent
19 84
20 application of TH successfully controlled his SE, and the pa- GOS score of 5, while another 2 patients (18.2%) died of 85
21 tient recovered with post-status epilepticus epilepsy. extreme brain edema or deep vein thrombosis with pulmo- 86
22 Patients E (6-month-old boy) and F (2-month-old boy) pre- nary embolization. The remaining 5 patients in the TH group 87
23 sented with head trauma owing to abuse. The SE in these (45.4%) had a GOS score of 4, which indicated that they had 88
24 patients continued despite decompressive craniectomy and recovered, with moderate functional disabilities. 2 of the 12 89
25 the administration of multiple AEDs. We applied TH along patients (16.6%) in the control group had a GOS score of 5. 1 90
26 with continuous midazolam infusions to both patients, and had a score of 4 (33.3%), 9 of the 12 patients had a GOS score of 91
27 the convulsions remitted within 24 h. However, although the 3 (75%). Comparisons of the GOS scores between the groups 92
28 93
SE was well controlled, patient E died of extreme brain edema. revealed that patients with RSE/SRSE who did not receive TH
29 94
exhibited significantly worse outcomes (GOS scores)
30 95
compared to patients who received TH (p < 0.05).
31 Control group 96
32 97
33 Another 12 patients presented with RSE/SRSE during the study Incidence of progression to post-status epilepticus epilepsy 98
34 period did not receive TH due to contraindications or financial As illustrated in Table 2, 5 of the 11 patients (45.4%) in the TH 99
35 restrictions. Therefore, we included these patients in the group developed chronic refractory epilepsy later in life. All 100
36 patients (100%) in the control group developed chronic re- 101
control group. Most patients in the control group had FIRES as
37 fractory epilepsy, causing severe functional disabilities. 102
the etiology (7/12, 58.3%).
38 Comparisons of the incidences between the groups revealed 103
39 that fewer patients in the TH group vs. the control group 104
40 Comparisons between the TH and control groups 105
progressed to post-status epilepticus epilepsy after 1- year
41 106
follow-up period. (p < 0.005).
42 Details regarding the comparisons of clinical information be- 107
43 tween the TH and control groups are shown in Table 2. As 108
44 109
shown in Table 2, no significant differences in age or AED
45 Discussion 110
46 111
47 Applying TH within 6 h after birth is considered a standard 112
48 Table 2 Outcome measurement between treatment-and 113
treatment for moderate to severe neonatal hypoxic ischemic
49 control-group. 114
encephalopathy [21]. Further, TH reportedly improves the
50 Treatment Control P value survival rate and neurologic outcome of neonatal hypoxic 115
51 Group(n ¼ 11) group (n ¼ 12) 116
ischemic encephalopathy survivors [17,18]. Although the
52 Age (yrs; median 6.5(9.8) 9(6.25) 0.30 117
precise mechanisms remain unclear, TH is thought to reduce
53 (IQR)) 118
epileptic discharges in patients with neonatal hypoxic
54 Sex (M/F) 9/2 7/5 0.092 119
55 ischemic encephalopathy [23]. Interestingly, TH also report- 120
RSE duration (hrs; 24(40) 96(90) 0.023*
56 median (IQR)) edly decreases brain activity in cardiac arrest patients post- 121
57 ICU stay (days; 30(42) 30.5(30.25) 0.666 resuscitation [24,25] and decreases intracranial pressure 122
58 median (IQR)) while preserving adequate cerebral perfusion in patients 123
59 AEDs kinds (median 5(3) 3(1.5) 0.086 with traumatic brain injury [26]. In animal studies, TH ex- 124
60 (IQR)) hibits attenuating effects on apoptosis [27] and mitigates the 125
61 GOS score (median 4(2) 3(0.75) 0.01*
altered extrahippocampal neurotransmitters in animals 126
62 (IQR))
with pilocarpine-induced SE [28]. Given these findings, TH is 127
63 Chronic Epilepsy 5(45) 12(100) 0.005** 128
(numbers, (%)) being considered an alternative, non-invasive physical
64 129
treatment option for cardiac arrest, traumatic brain injury,
65 Statistically significant P values are bolded. *P < 0.05; **P < 0.01. 130
and SE [29].

Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004
 BJ281_proof ■ 25 April 2020 ■ 6/8

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1 In a trial on adult patients with SE who were under me- 66

2 chanical ventilation in the ICU, adding TH to standard SE Conclusions 67
3 care did not result in better neurologic outcomes, but a 68
4 possible anticonvulsive effect was observed [30,31]. Howev- Collectively, our findings support that TH effectively shortens 69
5 the seizure duration in pediatric patients with RSE/SRSE. 70
er, research on the beneficial effects of TH for pediatric pa-
6 Although there were some manageable complications during 71
tients with SE is limited. Control of pharmaco-resistant RSE
7 TH, it was otherwise safe for use in pediatric patients with 72
after TH application was reported in several case series
8 RSE/SRSE. Our study provides evidence that shortened seizure 73
9 [2,31e33]. In pediatric patients with SE, age, seizure etiology, 74
and duration of SE all affect outcome [34]. Moreover, the durations in the acute symptomatic phase of SE can reduce
10 75
the occurrence of post-status epilepticus epilepsy and
11 timely administration of first-line benzodiazepines leads to a 76
12 lower death rate and risk of AED-infusion dependency [35]. improve patients’ long-term functional outcomes. 77
13 Nevertheless, efficient treatment options for controlling 78
14 pharmaco-resistant RSE are lacking in current clinical 79
15 practice. Institution(s) where the work was performed Q4 80
16 Several studies have shown that patients with short SE 81
17 Kaohsiung Chang Gung Memorial Hospital. 82
durations have better outcomes [36e39] owing to fewer SE-
18 83
related complications, such as tachycardia, hypoglycemia,
19 84
20 hypotension, or rhabdomyolysis, although a few studies 85
21 yielded inconclusive results [40]. Patients with acute symp- Declaration 86
22 tomatic SE have a three-fold greater risk of developing 87
23 chronic epilepsy compared to patients with acute symp- Part of the content of this article was presented at the 2nd 88
24 tomatic seizures [1]. Although the etiology for RSE/SRSE is congress of Pediatric Neurocritical care consortium, 8 June, 89
25 the pivotal predictor for RSE/SRSE outcome [30], the down- 2019, Taipei, Taiwan. 90
26 stream mechanisms of SE, including neuronal death, reac- 91
27 tive oxygen stress production, bloodebrain barrier 92
28 93
breakdown, and adenosine triphosphate depletion,
29 Conflicts of interest 94
contribute to the long-term consequences of SE, such as
30 95
chronic epilepsy and cognitive problems [2]. In our study,
31 None. 96
32 since the TH group had significantly shorter seizure dura- 97
33 tions than did controls, this may also have led to the 98
34 improved long-term functional outcomes and reduced 99
35 incidence of chronic epilepsy in the patients who received Acknowledgements 100
36 TH. Our data highlight the beneficial effects of TH on pa- 101
37 tients with RSE/SRSE, and are consistent with the data We appreciated the Biostatistics Center, Kaohsiung Chang 102
38 supporting the positive effects of TH on patients with car- Gung Memorial Hospital for statistics work. Q5 103
39 diac arrest. 104
40 105
Here, the most frequently observed complication was
41 106
electrolyte abnormalities. During TH, serum electrolyte dis- Appendix A. Supplementary data
42 107
43 turbances occur because of the increased renal excretion of 108
44 electrolytes and the resulting intracellular shift [41]. The most Supplementary data to this article can be found online at 109
45 common situation was hypokalemia, the clinical effects of https://doi.org/10.1016/j.bj.2020.04.004. 110
46 which include cardiac arrhythmias, muscle weakness, rhab- 111
47 domyolysis, renal failure, and elevated blood sugar levels (due 112
48 to the suppression of insulin secretion) [41]. Given the po- 113
Uncited references Q7
49 tential complications of electrolyte disturbances, preventing 114
50 electrolyte imbalances caused by hypothermia should be the 115
51 [22]. 116
clinician's main goal [42].
52 117
Several limitations of this study should be noted. First,
53 118
54
we had a relatively small sample size due to the high cost references 119
55 of receiving TH with the Artic Sun® temperature man- 120
56 agement system in Taiwan. Second, as this was a retro- 121
57 spective study, data collection was limited by the available [1] Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, 122
58 documentation. Third, we only utilized the GOS score, not Glauser T, et al. Guidelines for the evaluation and 123
59 a detailed neurologic outcome evaluation tool, to deter- management of status epilepticus. Neurocritical Care 124
60 mine outcome. Finally, the etiologies of RSE/SRSE were 2012;17:3e23. 125
61 diverse. Hence, we could not directly compare the out-
[2] Guilliams K, Rosen M, Buttram S, Zempel J, Pineda J, Miller B, 126
62 comes among the groups. These variables may be impor-
et al. Hypothermia for pediatric refractory status epilepticus. 127
63 Epilepsia 2013;54:1586e94. 128
tant contributors to outcome, and thus additional studies [3] Bayrlee A, Ganeshalingam N, Kurczewski L, Brophy GM.
64 129
with larger sample sizes that address these issues are Treatment of super-refractory status epilepticus. Curr Neurol
65 130
needed to confirm our findings. Neurosci Rep 2015;15:66.

Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004
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Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004
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Please cite this article as: Hsu M-H et al., Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-
status epilepticus epilepsy, Biomedical Journal, https://doi.org/10.1016/j.bj.2020.04.004