EXPERIMENTAL AND THERAPEUTIC MEDICINE

Brain hypothermia therapy for childhood acuteencephalopathy based on clinical evidence (Review)
GEORGE IMATAKA and OSAMU ARISAKA
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi 321‑0293, Japan
Received July 31, 2015; Accepted September 15, 2015
DOI: 10.3892/etm.2015.2760
Abstract. Although previous studies have reported on theeffectiveness of brain hypothermia therapy in childhood acuteencephalopathy, additional studies in this field are neces‑sary. In this review, we discussed brain hypothermia therapymethods for two clinical conditions for which sufficientevidences are currently available in the literature. The first
condition is known as hypoxic‑ischemic encephalopathy andoccurs in newborns and the second condition is acute encepha‑lopathy which occurs in adults following cardio­pulmonary
resuscitation associated with out‑of‑hospital cardiac arrest
state resulting from ventricular arrhythmia. Furthermore, we
assessed the prospects of applying these therapies to acuteencephalopathy in children.
Contents
1. Clinical evidence for brain hypothermia therapy
2. Treatment for brain hypothermia therapy of childhood
with the onset of acute encephalopathy
3. Conclusion
1. Clinical evidence for brain hypothermia therapy
Clinical reports have focused on the effectiveness of brain
hypothermia therapy for acute encephalopathy in children.
However, there is a lack of high‑quality studies with a large
number of cases that can show the effectiveness and safetyof clinical methods used in brain hypothermia therapy inchildhood acute encephalopathy. There are currently two
methods of therapy for which numerous high‑quality reports
are available in the literature. These studies mostly focused onCorrespondence to: Dr George Imataka, Department of Pediatrics,
Dokkyo Medical University School of Medicine, 880 Kitakobayashi,Mibu, Shimotsuga, Tochigi 321‑0293, JapanE‑mail: geo@dokkyomed.ac.jp

Key words: hypothermic therapy, child, status epilepticus, Targeted
temperature management, coolingbrain hypothermia therapy and reported on hypoxic‑ischemic
encephalopathy in newborns and acute encephalopathy inadults following cardiopulmonary resuscitation associatedwith out‑of‑hospital cardiac arrest state resulting from ventric‑ular arrhythmia.
Six large‑scale clinical studies focusing on hypoxic‑isch‑emic encephalopathy of newborns were reported during theperiod 2005‑2010. The studies were conducted mainly inwestern countries, China, and Oceania. One of these clinicalstudies was the TOBY trial which was conducted in 2009and included 163 cases (1). Investigators in the TOBY trial
performed body cooling for 72 h and reduced the temperature(rectal temperature) to 33˚C and 34˚C. The results revealed asignificant reduction in mortaligy or severe after‑effects after
18 months from the treatment (1). Follow‑up studies conductedduring the childhood period indicated improvements in thecognitive ability of the children involved (2).
In a report conducted on 100 cases in 2010 in China, thenasopharynx was cooled for 72 h at 34±0.2˚ using a selective
head cooling method (3). Results from that study showed asignificant difference in mortality and severe after effects
after 18 months (3). As a result, the brain hypothermia
therapy was recommended for childhood hypoxic‑ischemic
encephalopathy by the International Liaison Committee on
Resuscitation in 2010 (4).
Concerning the out‑of‑hospital cardiopulmonary arrest
state in adults, two high‑quality reports were published in2002. In one report, 275 patients were resuscitated from thecardiopulmonary arrest state. In that study 137 patients wereassigned to the hypothermia group and 138 to the normo‑
thermia group (5). Th difference in mortality rates after
6 months was compared between the two groups. The mortality
rates 6 months after cardiac arrest was 14 percentage points
lower in the hypothermia group than that in the normothermia
group, while 55% of patients in the hypothermia group had afavorable neurologic outcome, as compared with 39% in thenormothermia group. Authors of that study concluded that thesystemic cooling to a bladder temperature between 32˚C and34˚C for 24 h increased the chance of survival and produced afavorable neurologic outcome (5).
In the second study, 77 patients were assigned to treatment
with hypothermia or normothermia (6). Core body tempera‑ture of patients in the hypothermia group was reduced to33˚C within 2 h after the return of spontaneous circulationand maintained at that temperature for 12 h. Results from2

IMATAKA and ARISAKA: BRAIN HYPOTHERMIA THERAPY FOR CHILDHOOD ACUTE ENCEPHALOPATHY

that study revealed that the life prognosis improved in thehypothermia group (6). Authors of that study concluded
that induced hypothermia improved outcomes in comatose
patients after resuscitation from out‑of‑hospital cardiac
arrest (6). Consequently, in 2002, the American Heart
Association and the European Resuscitation Council recom‑
mended the brain hypothermia therapy as a viable treatment
following resuscitation from cardiopulmonary arrest state inadults.
However, few studies have reported brain hypothermia
therapy for childhood acute encephalopathy. Studies
conducted on the effectiveness of brain hypothermia therapy
for childhood acute encephalopathy exist only at the casereport level, and a large‑scale clinical research report
has yet to be performed. In one clinical study reportingon brain hypothermia therapy in 38 children, caused byout‑of‑hospital cardiac arrest, the clinical effects were notconfirmed (7). Acute encephalopathy is an aspect of thisdisease with a broad spectrum of symptoms including avariety of pathological conditions (such as fever, infection,epilepsy, immunological abnormalities, metabolic issues,
hypoxia and genetic factors) caused by brain dysfunction.
In childhood acute encephalopathy, therefore, it is preferable
to select a treatment method according to its class and theseverity of the complication.
In another case report on brain hypothermia therapy theauthors reported about a noteworthy outcome in an infant
with epilepticus‑type acute encephalopathy who sufferedfrom cardiac arrest and cardiopulmonary resuscitation (8).
The results reported in that study were very encouraging andmay lead to more discussions and even initiate additional
studies in future.
2. Treatment for brain hypothermia therapy of childhood
with the onset of acute encephalopathy
The method of brain hypothermia therapy for children has yet
to be widely introduced as a viable type of treatment. There is
only one protocol report on the method of brain hypothermia
therapy for children (9). This protocol report was develo­ped ina single facility, without establishing any standard treatment
method or safety precautions. Therapy using various drugs,
such as pulse steroids, high-dose γ‑globulin and anticonvul‑
sants was used in combination for brain hypothermia (9);however, no study group has conducted a comparative study
on the clinical effects of these medications.
The specifics of brain hypothermia therapy in childhood
acute encephalopathy remain to be determiend. For example,
we do not have a complete understanding regarding the mostefficient temperature or the most effective treatment period
duration that should be used for patients such as children.
In a multi‑facility cooperative study conducted in Europeand Australia, a study on 950 cases of adults suffering fromacute brain disorder following cardiac arrest was conductedin order to compare their prognosis after 6 months (10).
The targeted control body temperatures were divided into
two groups with a temperature of 33˚C and 36˚C. The dataobtained from these groups were compared. Results of thatstudy reported no substantial amelioration in the prognosis
in the groups investigated (10).

Based on the results obtained in the abovementioned
study, the brain normal‑temperature method or targeted
temperature management (TTM) has been recentlyattempted as a practical treatment method for childhood
acute encephalopathy. Brain normal‑temperature method or
TTM were also employed as treatment methods for main‑taining the brain or body temperature at 36˚ (11). Currently,
however, this procedure remains at the investigation stage,
while there is no evidence indicating the obvious effective‑
ness of TTM.
When applying brain hypothermia therapy to childhood
acute encephalopathy, the timing and safety from the onsetof acute encephalopathy until brain hypothermia therapy
commences should be also studied satisfactorily. During
the early phase of the childhood acute encephalopathy, thedamage to the brain is more severe. This damage increases
the risk of secondary disorders such as delayed energy
production and defective energy utilization, neuronal edema,and cerebral blood flow perfusion abnormality (9). Therefore,
the therapeutic time window (TTW) is limited and there is
only a narrow time window to treat severe acute encepha‑lopathy effectively (10). A study on TTW was conducted in
10 Japanese facilities equipped with a pediatric intensive
care unit (PICU) (12). The Japanese study group worked on
43 cases of which 27 were submitted to mild hypothermia and16 cases to normothermia.
Brain hypothermia therapy was conducted on children
with acute encephalitis and acute encephalopathy. Children
were subjected to the brain hypothermia therapy for 48 h using
the whole body cooling system to set the body temperature
at 33.5‑35˚C (12). Results from that study demonstrated thatbrain hypothermia therapy in the early stage of the diseasesignificantly improves the neurological prognosis (12).
A contradictory report offer evidence on the poor prognosisof brain hypothermia therapy in the early stage of disease (13)making the selection of an appropriate therapeutic method achallenge. Brain hypothermia therapy in children is a treatmentthat should be performed in highly advanced medical facilities
or intensive care rooms in order to provide optimal care andmonitoring facilities.
In the brain hypothermia therapy whole‑body manage‑
ment at the PICU level is required. In some cases of brain
hypothermia therapy, steroid pulse therapy, γ ‑globulin
therapy, and intravenous therapy of various anti‑seizure
drugs are often used together (9). Therefore, to confirm theclinical effects of this therapy, it is essential to study theclinical courses of treatment by dividing the cases into twogroups: i) group being administered the brain hypothermia
therapy alone and ii) group receiving the treatment using
the concomitant drugs. The number of studies conductedon this subject are currently insufficient. Informed consent,
however, remains a determining factor in studies on brain
hypothermia therapy.
3. Conclusion
As there are many cases with good prognosis using medicaltherapy alone in childhood acute encephalopathy, overtreat‑ment must be sufficiently taken into consideration whenselecting brain hypothermia therapy. In future, in order toEXPERIMENTAL AND THERAPEUTIC MEDICINE

determine the effects and prognosis of the brain hypothermia
therapy for acute encephalopathy with a broad spectrum ofsymptoms including the epilepticus‑type encephalopathy
in children, evidence worthy of the objective evaluation inaccordance with the clinical symptoms should be obtained
and assessed.
References
1. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL,Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, et al;
TOBY Study Group: Moderate hypothermia to treat perinatal
asphyxial encephalopathy. N Engl J Med 361: 1349‑1358, 2009.
2. Azzopardi D, Strohm B, Marlow N, Brocklehurst P,Deierl A, Eddama O, Goodwin J, Halliday HL, Juszczak E,Kapellou O, et al; TOBY Study Group: Effects of hypothermia
for perinatal asphyxia on childhood outcomes. N Engl J Med 371:
140‑149, 2014.
3. Zhou WH, Cheng GQ, Shao XM, Liu XZ, Shan RB, Zhuang DY,Zhou CL, Du LZ, Cao Y, Yang Q, Wang LS; China Study
Group: Selective head cooling with mild systemic hypothermia
after neonatal hypoxic‑ischemic encephalopathy: A multicenter
randomized controlled trial in China. J Pediatr 157: 367‑372,
372.e1‑3, 2010.
4. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L,
Goldsmith JP, Guinsburg R, Hazinski MF, Morley C,
Richmond S, et al; Neonatal Resuscitation Chapter Collaborators:
Part 11: Neonatal resuscitation: 2010 International consensus oncardiopulmonary resuscitation and emergency cardiovascularcare science with treatment recommendations. Circulation 122(16Suppl 2): S516‑S538, 2010.
5. Hypothermia after Cardiac Arrest Study Group: Mild therapeutic
hypothermia to improve the neurologic outcome after cardiac
arrest. N Engl J Med 346: 549‑556, 2002.

3

6. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W,
Gutteridge G and Smith K: Treatment of comatose survivors ofout‑of‑hospital cardiac arrest with induced hypothermia. N EnglJ Med 346: 557‑563, 2002.
7. Moler FW, Silverstein FS, Holubkov R, Slomine BS,Christensen JR, Nadkarni VM, Meert KL, Clark AE,Browning B, Pemberton VL, et al; THAPCA trial investigators:
therapeutic hypothermia after out‑of‑hospital cardiac arrest inchildren. N Engl J Med 372: 1898‑1908, 2015.
8. Imataka G, Tsuboi Y, Kano Y, Ogino K, Tsuchioka T, Ohnishi T,Kaji Y, Wake K, Ichikawa G, Suzumura H, et al: Treatment
with mild brain hypothermia for cardiopulmonary resuscitation
after myoclonic seizures in infant with robertsonian type oftrisomy 13. Eur Rev Med Pharmacol Sci 19: 2852‑2855, 2015.
9. Imataka G, Wake K, Yamanouchi H, Ono K and Arisaka O:
Brain hypothermia therapy for status epilepticus in childhood.
Eur Rev Med Pharmacol Sci 18: 1883‑1888, 2014.
10. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y,
Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, et al;
TTM Trial Investigators: Targeted temperature management
at 33˚C versus 36˚C after cardiac arrest. N Engl J Med 369:2197‑2206, 2013.
11. Nishiyama M, Tanaka T, Fujita K, Maruyama A and Nagase H:
Targeted temperature management of acute encephalopathy
without AST elevation. Brain Dev 37: 328‑333, 2015.
12. Kawano G, Iwata O, Iwata S, Kawano K, Obu K, Kuki I, Rinka H,Shiomi M, Yamanouchi H, Kakuma T, et al; Research Network
for Acute Encephalopathy in Childhood: Determinants ofoutcomes following acute child encephalopathy and encephalitis:
Pivotal effect of early and delayed cooling. Arch Dis Child 96:
936‑941, 2011.
13. Imataka G, Wake K, Suzuki M, Yamanouchi H and Arisaka O:
Acute encephalopathy associated with hemolytic uremic
syndrome caused by Escherichia coli O157: H7 and rotavirus
infection. Eur Rev Med Pharmacol Sci 19: 1842‑1844, 2015.