paper 3658

European Review for Medical and Pharmacological Sciences

2014; 18: 1883-1888

Brain hypothermia therapy for statusepilepticus in childhood
G. IMATAKA, K. WAKE1, H. YAMANOUCHI2, K. ONO1, O. ARISAKA
Department of Pediatrics; Dokkyo Medical University School of Medicine, Tochigi, Japan1
Department of Emergency and Critical Care Medicine; Dokkyo Medical University School of
Medicine, Tochigi, Japan2
Department of Pediatrics; Saitama Medical University, Saitama, Japan

Abstract. – OBJECTIVE: At the Dokkyo Medical University Hospital, we introduced a brain
hypothermia therapy protocol for treating childhood status epilepticus and acute encephalitis/encephalopathy in 2004.
PATIENTS AND METHODS: This protocol focuses on infants with a minimum age of six
months or 7.5 kg in weight. Applicable diseases
include acute encephalitis/encephalopathy occurring from status epilepticus or seizures lasting for 30 minutes or longer, in cases such asnear drowning, hypoxic-ischemic encephalopathy, post-resuscitation encephalopathy, cardiorespiratory arrest, severe head injury, or otherdiagnoses in which the pediatric neurologist recognizes the possibility of neurological complications. Brain hypothermia therapy is managed
within the intensive care unit (ICU).
RESULTS: The target body temperature is a
bladder or rectum temperature of 34.0 to 35.0 degrees. This body temperature is reduced to thetarget temperature within six hours of theseizures. Hypothermia is maintained for 48 hours
and concomitant steroid pulse therapy may be
used at appropriate times. Sodium thiopental isused to sedate and rewarming is carried out at 0.5
degrees per 12 hours. Osmotic diuretics, muscle
relaxants and circulatory antagonists may beconcomitantly used at appropriate times.
CONCLUSIONS: This paper reviews the brain
hypothermia therapy protocol.
Key Words:
Hypothermia, Steroid pulse, Status epileptcus,
Acute encephalopathy, Protocol.

Outline of Brain Hypothermia Therapy
Cool temperatures are an effective method forpreserving cadavers. Conventionally, human beings have understood that “cooling things” offersa range of benefits. In medicine, cooling methods
have been used in response to the onset of fever

for over two thousand years. In ancient Greece,
Hippocrates treated head injuries amongst thesoldiers by cooling them with snow. Since the1800s, researchers have been observing mammals in hibernation, and the resuscitating humans
by covering them with snow has been attemptedin Russia.
In modern-day medicine, a cancer treatment
involving the cooling of cancer patients’ bodytemperatures to 32 degrees to inhibit the proliferation of cancer cells was reported in 1940 in
the USA 1 . Subsequently, cooling the wholebody was used as a treatment for serious head
injuries. During the 1950s, its benefits duringopen-heart surgery were reported2. During thatsame period, doctors began to notice the benefits of cooling in resuscitation. In 1962, Westin,in Sweden reported resuscitating babies born ina hypoxic state by placing them in cold water
until they began to breathe 3. In 1963, a man
who nearly drowned in a river in Norway, andwhose heart stopped, was resuscitated and subsequently fell into an accidental hypothermic
state, from which he recovered without complications after six months in ICU4. Since this occurred, research for this particular therapy has
gained momentum.
During the 1980s, researchers gathered evidence that the cerebral-neuroprotective action ofcooling body temperature to 34 degrees in animalmodels was effective. In 1990, a mechanism was
proposed to adjust the brain temperature underwhole-body management, after which its clinicalapplications began in earnest. In 2002, an article
was published explaining the clinical effectiveness of the brain hypothermia with regard to outof-hospital cardiac arrest among adults5,6, and in
the same year, the American Heart Association(AHA) and the European Resuscitation Council(ERC) recommended brain hypothermia therapy
for the treatment of cardio-respiratory arrest. In

Corresponding Author: George Imataka, MD; e-mail: geo@dokkyomed.ac.jp

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G. Imataka, K. Wake, H. Yamanouchi, K. Ono, O. Arisaka

2010, the International Liaison Committee on
Resuscitation (ILCOR) recommended the implementation of hypothermia therapy for newborns
in neonatal hypoxic-ischemic encephalopathy
cases7.
Physiological Changes and Treatment
Strategies in Status Epilepticus
and Acute Encephalopathy
A wide range of acute encephalopathy conditions, including acute necrotizing encephalopathy(ANE)8, acute encephalopathy with febrile convulsive status epilepticus (AEFCSE)9, acute infantile encephalopathy predominantly affecting
the frontal lobes (AIEF)10, acute encephalopathy
with biphasic seizures and late reduced diffusion(AESD) 11 , clinically mild encephalitis/encephalopathy with a reversible splenial lesion(MERS)12, and acute encephalitis with refractory,
repetitive, partial seizures (AERRPS)13, which isan acute encephalopathy accompanied seizure
excitotoxicity, have been proposed and detailed
breakdowns considered. The main symptom
across the acute encephalopathy spectrum is status epilepticus.
Physiological changes that accompany statusepilepticus occur not only in the central nerves.
In status epilepticus cases, increased blood flow
is localized, leading to increased demand foroxygen consumption and glucose metabolism
and resulting in the patient potentially developing
brain edema or cerebral ischemia. This type ofstatus epilepticus can occur against a backgroundof excitotoxicity in nerve cells, mitochondrial
dysfunction, and hypercytokinemia. Furthermore, secondary long seizures can trigger excessive release of glutamic acid, accumulation offree radicals or oxidant stress, mitochondrial beta-oxidation disorders, and caspase activation,
evoking subsequent, delayed neurocyte apoptosis
and glial generation.
Accordingly, treatment of status epilepticus involves stopping the occurrence of multiple
seizures, implementing cerebroprotective therapy, and preventing brain hypertension, as well as
maintaining blood pressure and dynamic circulation, respiratory management to prevent hypoxemia and hypercapnia, fluid infusion to correct
acidosis and electrolytes and manage blood sugar. As such, the whole-body management must
be thoroughly implemented subsequently to theoccurrence of status epilepticus. Furthermore,1884

brain hypothermia therapy, is expected to be effective against delayed neurocyte disorders after
status epilepticus.
Observations Related to theProtective Effect of Brain Cell
Protection During Brain Hypothermia
Cooling the brain is known to have a range ofprotective benefits with regard to neurocytes.
Low body temperature reduces brain activity, but
at the same time controls brain metabolism and isbeneficial to reducing the consumption of oxygen, fructose, adenosine triphosphate. When applied in conditions causing cellular edema suchas status epilepticus and acute encephalopathy, it
can not only prevent reperfusion injury, but also
improve the homeostasis of Ca2+ in the brain,
thereby, reducing damage to brain neurocytes.
Furthermore, a low temperature state is effective
in maintaining glutamic acid concentration andhypostasis between neurocytes. In addition, in astate of cerebral ischemia it has been reported
that it may prevent an increase in free radicals, inaddition to preventing irreversible delayed neurocyte-damaging apoptosis5-7. As such, brain hypothermia therapy shows promise in minimizing
the mechanisms that evoke delayed neurocyte
damage subsequent to status epilepticus.
Implementation of Brain
Hypothermia Therapy
At the hospital, we developed a protocol for abrain hypothermia therapy for the treating childhood status epilepticus and acute encephalitis/encephalopathy in 2004. The process by which we
implement low body temperature therapy is asfollows. A doctor accompanying the helicoptertransferring the infant with seizures, administers
first-line anti-seizure medication (Dormicum, either via nasal cavity or intravenously). When thehelicopter delivers the doctor and patient to theemergency unit examining room, the second-line
drug (Fosphenytoin or intravenous Phenobarbital) is administered. Complex cases, in which thepatient resists these treatments and multiple
seizures occur, are then referred for brain hypothermia therapy.
This protocol (Table I) is applied to cases ofacute encephalitis/encephalopathy occurring as aresult of status epilepticus or seizures lasting forBrain hypothermia therapy
Table I. Proposed protocol for brain hypothermia therapy (Dokkyo Medical University Hospital ICU: April 2014).
Anti-seizure medication treatment for status epilepticusA) Midazolam (0.5 mg/kg) administered via the nasal cavity or cheek mucosa
B) Midazolam (0.15 mg/kg) intravenously (i.v.) administered (up to two doses possible)C) Between ages 0 and 2: intravenous phenobarbital, between 15 and 20 mg/kg (10 minsi.v.), 2 years or older: Fosphenytoin 22.5 mg/kg (10 minsi.v.)
D) Sodium thiopental between 3 and 5 mg/kg (slow i.v.)
Brain hypothermia therapy
This protocol applies to infants weighing 7.5 kg or over, aged 6 months or older.
Introductory period
1. Status epilepticus/acute encephalopathy admission: ICU (request for admission), contact brainwave dept/radiology(brain and chest CT)
2. Check vital signs, establish a peripheral line
3. Establish central venous line: establish double/triple lumen catheter + arterial line
4. Fluid infusion between 80 and 100 ml/kg/day: under whole-body management, fluid control must not be reduced morethan necessary in order to maintain blood pressure and cerebral circulation. Blood pressure is evaluated using an arterialpressure monitor. Maintenance fluids comprise an acetic acid preparation maintenance fluid and a lactic acid preparation.
Vitamins are administered. When theophylline is administered, vitamin B6 is measured (light-shielding blood collection
tube: administer vitamin B6 for theophylline-related seizures. Take care not to induce cardiac arrest by sudden administration of B6).
5. Management of blood count, electrolytes, blood sugars, albumin, clotting value. Ferritin, IL-2R, β2MG, procalcitonin,
immune globulin, etc. submitted.
6. Mannitol 3-5 ml/kg × 4-6 times/day (administered over an hour).
7. Harvest spinal fluid (after first administration of mannitol). General spinal fluid + various cytokines (IL-6, IL-1β,
TNF-α), Tau protein, submitted. Freeze and store the remaining fluid at -80 degrees.
8. If possible time/wise implement MRI (DWI/ADC-map).
9. Intratracheal intubation (if difficult, use muscle relaxant or inhalation anesthetic)
10. Artificial ventilation: PCO2 at 35 to 40 mmHg (do not over-ventilate). PEEP kept slightly low taking brain hypertension into consideration. Raise head 10 degrees. If brain hypertension occurs: request placement of cerebral pressure
monitor by neurosurgeon.
11. Steroid pulse therapy: methylprednisolone 30 mg/kg over two hours for three days, during which heparin or fragmin
therapy is continued. APTT 1.5 or above.
12. Administer famotidine 0.5 mg/kg twice, or alternatively, omeprazole.
13. Brain hypothermia therapy use a whole-body blanket-cooling method, to induce target body temperature (direct intestine/bladder temperature 34.0 to 35.0 degrees) within six hours of onset. If necessary, cool the head or wash the stomach with normal saline solution while taking care not to cause electrolyte abnormalities, or use chilled fluid infusion.
14. Anti-seizure medication:sodium thiopental, 5-10 mg/kg/hr (if this cannot be used, consider midazolam, 0.3 to 0.9 mg/kg/hr).
15. Sedation depth should be confirmed by portable electroencephalograph/paperless electroencephalograph (Makin2) asreaching suppression burst within six hours of beginning therapy.
Cooling period
16. Target temperature to be maintained for 48 hours (or maximum 72 hours). Confirm BIS monitor value at suppression
burst (aim for 40 or below) and adjust the sodium thiopentaldose administered based on the BIS value as appropriate.
Cases achieving a positive sedation depth should have their sodium thiopental dose reduced prior to rewarming at a
BIS value between 60 and 70, and at body temperature 35.0 degrees.
[Caution] If spikes remain with suppression bursts, consider complete suppression (pupils will constrict to mydriasis,and response to light is lost: BIS value of 20 or lower).
17. UseINVOSTM at an appropriate time to check oxygen saturation at the left and right front scalp, to evaluate brain circulation.
18. Blood pressure maintenance: appropriate dose of dopamine hydrochloride (5 µg/kg/min = 0.3 mg/kg/h = 0.015 ml/kg/h),manage electrolyte abnormalities and blood glucose. Heart rate will fall to bradycardia with falling body temperature.
19. Administer antibacterials as appropriate. In applicable conditions, cerebroprotectiveedaravone, sivelestat Na as a neutrophil elastase inhibitor, and aciclovir.
Rewarming period
20. Rewarming is implemented at a pace of 0.5 degrees per 12 hours. Care should be taken to avoid pneumonia in linewith increased sputum secretions. Aim to remove the patient from artificial respiration on the 5th to 7th day. For cases
in which laryngitis is likely, intravenous dexamethasone or epinephrine should be administered prior to removal of thetube.
21. For cases in which critical complications are envisaged, TRH therapy should be initiated at an early stage.
22. Including rehabilitation, aim to discharge the patient one month after onset.
23. Prior to discharge, evaluate brain waves, implement neuroradiological images/nuclear medicine tests and assess development. Where necessary, anti-seizure mediation should be periodically administered for preventative purposes.

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G. Imataka, K. Wake, H. Yamanouchi, K. Ono, O. Arisaka

30 minutes or more. These cases include neardrowning, hypoxic-ischemic encephalopathy,
post-resuscitation encephalopathy, cardio-respiratory arrest, severe head injury, or other diagnoses in which the pediatric neurologist recognizes a possibility of neurological complications.
Introductory Period
Brain hypothermia therapy is implemented in
the Intensive Care Unit (ICU), where a target
body temperature equivalent to bladder temperature between 34.0 and 35.0 degrees is induced
using a catheter with a temperature sensor attached, within six hours of the occurrence of status epilepticus. If this body temperature is difficult to achieve, chilled fluid transfusion or
chilled water injected via a gastric tube may be
used. The use of muscle relaxants is effective incontrolling the shivering. Strict care is required,however, to monitor the brain waves, as there is apossibility that non-convulsive status may be
missed. Sedation is administered using 5 to 10
mg/kg sodium thiopental per hour, under wholebody management, and within six hours of theoccurrence. The depth of sedation should be induced at which suppression and burst can beachieved, while monitoring the brain waves. If anelectroencephalograph is not available in the
ICU, the Makin2 (manufactured by GMS) paperless portable electroencephalograph, or the bispectral index (BIS) monitor (manufactured by
COVIDIEN, Dublin, Ireland) may be used. Brainwave suppression and burst is achieved at a BIS
value of 40 or lower 14. If there are multiple
spikes mixed in with burst waveforms, the sedation depth is lowered further to complete suppression (flat brain waves), at a BIS value of 20
or lower. In such cases, the left and right pupils
will constrict to mydriasis at 4 mm or above, andresponse to light is lost. For cases in which cerebral blood vessel damage or cerebral edema
causes brain oxygen metabolism issues, the noninvasive mixed oxygen saturation monitoring device INVOSTM (manufactured by COVIDIEN)
used in brain or cardiac surgery may be used on
the scalp to monitor localized brain perfusion irregularities, ischemia and oxygen trends. Cases
in which stable sedation cannot be achieved using sodium thiopental require the cooperation ofan anesthetist, who will administer a mixture ofoxygen and isoflurane or sevoflurane at between
1 and 2 MAC (1.15-2.3%), inducing suppression
and burst within a few minutes.
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Cooling Period
Cooling is done using a whole-body coolingblanket (manufactured by MAC8). The standard
required cooling period is 48 hours, which is extended to 72 hours if required. Depending on thesymptoms, the head may also be cooled. Conditions diagnosed against a background of hypercytokinemia are administered with steroid pulse
therapy, using 30 mg/kg methylprednisolone forthree days. In addition to managing sufficient fluid transfusion to maintain brain circulation, an
osmotic diuretic and a circulator antagonist may
be used as appropriate. In cases where significant
brain hypertension is noted, a neurosurgeon isconsulted and an intracranial pressure monitor
may be used.
Rewarming Period
Rewarming is done at a pace of 0.5 degrees
per 12 hours. Brain hypothermia therapy is implemented in partnership between a dedicated
ICU physician and a pediatrician (Figure 1).
Points to Note With Regard to
Brain Hypothermia Therapy
A range of adverse effects can occur as a resultof the changes in vital signs accompanying a reduction in body temperature. For this reason, themanagement of anesthesia, respiration, circulation, intracranial pressure, body temperature,must be monitored and the patient placed on artificial respiration. It is, therefore, imperative thatthe case be managed by ICU. Potential complications include hypotension, arrhythmia, electrolyte abnormality, hyperglycemia, edema of thelarynx, pulmonary atelectasis, cutaneous ulceration, pressure ulcers, and reduced white blood
cell count, clotting fibrinolytic disorders, reduced
immunity and increased susceptibility to infection, among others.

Conclusions
Sufficient evidence exists to demonstrate theprotective effects of brain hypothermia on brainneurocytes. The clinical benefits of brain hypothermia therapy have still not been establishedfor status epilepticus and acute encephalopathy.
Recently, reports have begun to appear15-17 suggesting the effectiveness of brain hypothermia
therapy for childhood seizure disorders. Hopeful-Brain hypothermia therapy

Figure I. Clinical course of brain hypothermia therapy (cooling period: 48 hours).

ly, clinical applications for brain hypothermia
therapy will be established in the near future,
thereby eliminating neurological complications
related to infant status epilepticus.
––––––––––––––––––––
Acknowledgements

We would like to express our deep gratitude and appreciation to
Drs Katashio H, Mitsui M, Tsukada K and Tsuboi T for theirvaluable guidance and supervision..

–––––––––––––––––-––––
Conflict of Interest

The Authors declare that there are no conflicts of interest.

References
1) FAY T. Observations on prolonged human refrigeration. New York State J Med 1940; 40: 347348.
2) SEALY WC, BROWN IW, YOUNG WG. A report on theuse of both extracorporeal circulation and hypothermia for open heart surgery. Ann Surg 1958;
147: 603-613.
3) WESTIN B, NYBERG R, MILLER JA. Hypothermia andtransfusion with oxygenated blood in the treatment of asphyxia neonatorum. Acta Paediatr
1962; Suppl 139: 1-80.
4) KVITTINGEN TD, NAESSE A. Recovery from drowningin fresh water. Br Med J 1963; 18: 1315-1317.

5) BERNARD SA, GRAY TW, BUIST MD. Treatment of comatose survivors of out-of-hospital cardiac arrestwith induced hypothermia. N Engl J Med 2002;
346: 557-563.
6) HOLZER M. Targeted temperature management for
comatose survivors of cardiac arrest. N Engl J
Med 2010; 363: 1256-1264.
7) P ERLMAN JM, W YLLIE J, K ATTWINKEL J, ATKINS DL,
CHAMEIDES L, GOLDSMITH JP, GUINSBURG R, HAZINSKI
MF, MORLEY C, RICHMOND S, SIMON WM, SINGHAL N,SZYLD E, TAMURA M, VELAPHI S. Neonatal Resuscitation Chapter Collaborators. Part 11: Neonatal resuscitation: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010; 122: S516-S538.
8) BERGAMINO L, CAPRA V,BIANCHERI R, ROSSI A, TACCHELLA A, AMBROSINI L, MIZUGUCHI M, SAITOH M, MARAZZIMG. Immunomodulatory therapy in recurrent
acutenecrotizing encephalopathy ANE: is it useful? Brain Dev 2012; 34: 384-391.
9) YAMANOUCHI H. Acute encephalopathy with febrile
convulsive status epilepticus (AEFCSE). Nihon
Rinsho 2011; 69:471-476.
10) YAMANOUCHI H, MIZUGUCHI M. Acute infantile encephalopathy predominantly affecting the frontal
lobes (AIEF): a novel clinical category and its tentative diagnostic criteria. Epilepsy Res 2006;
70(Suppl 1): S263-S268.
11) WATANABE Y, MOTOI H, OYAMA Y, ICHIKAWA K, TAKESHITA
S, MORI M, NEZU A, YOKOTA S. Cyclosporine for
acute encephalopathy with biphasic seizures andlate reduced diffusion. Pediatr Int 2014 Jan 13.
Doi: 10.1111/ped.12288. [Epub ahead of print]

1887

G. Imataka, K. Wake, H. Yamanouchi, K. Ono, O. Arisaka12) M I YATA R, T A N U M A N, H AYA S H I M, I M A M U R A T,
TAKANASHI J, NAGATA R, OKUMURA A, KASHII H, TOMITA
S, KUMADA S, KUBOTA M. Oxidative stress in patients with mild encephalitis/encephalopathy witha reversible splenial lesion (MERS). Brain Dev
2012; 34: 124-127.
13) WAKAMOTO H, TAKAHASHI Y, EBIHARA T, OKAMOTO K,
H AYASHI M, I CHIYAMA T, I SHII E. An immunologic
case study of acute encephalitis with refractory,
repetitive partial seizures. Brain Dev 2012; 34:
763-767.
14) D AHABA AA. Different conditions that could result in the bispectral index indicating an incor-

1888

rect hypnotic state. Anesth Analg 2005; 101:765-773.
15) KAWANO G, IWATO O, IWATO S, KAWAN K. Determinants of outcomes followingacute child encephalopathy and encephalitis: pivotal effect ofearly and delayed cooling. Arch Dis Child 2011;
96: 936-941.
16) R OSSETTI AO. What is value of hypothermia inacute neurologic diseases and status epilepticus?
Epilepsia 2011; 52(Suppl 8): 64-66.
17) GUILLIAMS K, ROSEN M, BUTTRAM S, ZEMPEL J. Hypothermia for pediatric refractory status epilepticus. Epilepsia 2013; 54: 1586-1594.