4.964

ReviewBrain Hypothermia Therapy andTargeted TemperatureManagement for Acute
Encephalopathy in Children: Status
and Prospects
George Imataka, Yuji Fujita, Jin Kikuchi, Koji Wake, Kazuyuki Ono and Shigemi Yoshihara

Special Issue
Clinical Management and Challenges of Encephalopathy and Encephalitis
Edited by
Dr. George Imataka

https://doi.org/10.3390/jcm12062095

Journal of

Clinical Medicine
ReviewBrain Hypothermia Therapy and Targeted TemperatureManagement for Acute Encephalopathy in Children: Status
and Prospects
George Imataka 1, * , Yuji Fujita 1 , Jin Kikuchi 2 , Koji Wake 2 , Kazuyuki Ono 2 and Shigemi Yoshihara 1
1
2*

Citation: Imataka, G.; Fujita, Y.;
Kikuchi, J.; Wake, K.; Ono, K.;
Yoshihara, S. Brain Hypothermia
Therapy and Targeted TemperatureManagement for Acute

Department of Pediatrics, Dokkyo Medical University, 880 Kitakobayashi,Mibu, Shimotsuga, Tochigi 321-0293, Japan
Department of Emergency and Critical Care Medicine, Dokkyo Medical University, 880 Kitakobayashi,Mibu, Shimotsuga, Tochigi 321-0293, Japan
Correspondence: geo@dokkyomed.ac.jp; Tel.: +81-282-86-1111

Abstract: In adult intensive care, brain hypothermia therapy (BHT) was reported to be effective inneuroprotection after resuscitation and cardiac arrest. By contrast, in neonatal intensive care, thepathophysiology of brain damage caused by hypoxic–ischemic encephalopathy (HIE) is attributed tocirculatory disturbances resulting from ischemia/reperfusion, for which neonatal brain cryotherapy
is used. The International Liaison Committee on Resuscitation, 2010, recommends cerebral cryotherapy
for HIE associated with severe neonatal pseudoparenchyma death. The usefulness of BHT forneuroprotection in infants and children, especially in pediatric acute encephalopathy, is expected.
Theoretically, BHT could be useful in basic medical science and animal experiments. However, there
are limitations in clinical planning for treating pediatric acute encephalopathy. No international
collaborative study has been conducted, and no clinical evidence exists for neuroprotection using BHT.
In this review, we will discuss the pathogenesis of neuronal damage in hypoxic and hypoperfusedbrains; the history of BHT, its effects, and mechanisms of action; the success of BHT; cooling andmonitoring methods of BHT; adverse reactions to BHT; literature on BHT. We will review the latest
literature on targeted temperature management, which is used for maintaining and controlling bodytemperature in adults in intensive care. Finally, we will discuss the development of BHT and targeted
temperature management as treatments for pediatric acute encephalopathy.
Keywords: brain hypothermia therapy; target temperature management; neuronal protection; hibernation

Encephalopathy in Children: Status
and Prospects. J. Clin. Med. 2023, 12,2095. https://doi.org/10.3390/
jcm12062095
Academic Editor: Maria A. Poca
Received: 27 December 2022
Revised: 28 February 2023
Accepted: 5 March 2023
Published: 7 March 2023

Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction
Acute encephalopathy in childhood and adolescence refers to a pathobiological condition of the brain that progresses rapidly. It is characterized by central nervous system(CNS) dysfunction caused by diffuse or widespread noninflammatory cerebral edema [1].
According to the recommendations of the Japanese Society of Child Neurology for acuteencephalopathy in children and infants, the impairment of consciousness must last for atleast 24 h and have a Glasgow coma score of 11 or less [2].
Several encephalopathy disorders are multifactorial, whereas others, such as previous
viral infections or hepatic or uremic encephalopathies, have a well-known etiology. The
influenza virus is the most common pathogen in Japan, followed by human herpesvirus
6, rotavirus, and respiratory syncytial virus. In recent years, the number of cases ofacute encephalopathy associated with other viruses, such as human metapneumovirus,
rhinovirus, and cytomegalovirus, has increased [3,4]. In acute encephalopathy syndrome,acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was themost common type (29%), Middle East respiratory syndrome (MERS) was the second mostcommon type (16%), and acute necrotizing encephalopathy (ANE) was the least common
type (4%). Other syndromes that occurred in 2% of cases included hemorrhagic shock

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encephalopathy syndrome (HSES) [3]. Although having a lower annual incidence, thenumber of cases of acute encephalopathy in Japan is significantly higher than in Westerncountries [5]. There have also been several reports of children infected with COVID-19
developing encephalitis, ANE, acute disseminated encephalomyelitis (ADEM), cytotoxic
lesion of the callosal splenium, posterior reversible encephalopathy syndrome (PRES), andother neurological illnesses.
The primary pathomechanism of acute encephalopathy is classified into four categories: metabolic error, cytokine storm, excitotoxicity, and unknown mechanisms. Noninflammatory brain edema is a pathologic feature of acute encephalopathy. Noninflammatory
brain edema raises intracranial pressure, resulting in decreased cerebral perfusion pressure,and eventually, herniation syndromes and brainstem dysfunction caused by CNS-mediatedrespiratory and circulatory failures [6–8]. Whatever the cause of encephalopathy, all casesof acute encephalopathy have at least one symptom—an altered mental state. The alteredmental state can be subtle and develop gradually, such as apraxia, including the inability
to sketch simple drawings, or it can be obvious and develop rapidly, leading to coma
or death within minutes. Inattention, poor judgment, and poor motor coordination are
symptoms of disturbed mental status. Seizures are common in many people, and they
are frequently febrile and last for an extended period (febrile status epilepticus). Febrile
status convulsions, status febrile seizures, and status febrile epilepticus associated withfever are triggers for the increasingly reported AESD [9], which is one of the common typesof acute encephalopathy. However, there is little evidence for identifying and treating
acute encephalopathy, despite the relatively high rate of morbidity and mortality linked
with the condition [6]. Moreover, neurological complications are also common in coronavirus disease 2019 (COVID-19) patients. COVID-19-associated multisystem inflammatory
syndrome in children (MIS-C) can cause cerebrovascular events as well as abnormal eye
movements. There have also been several reports of children infected with COVID-19
developing encephalitis, ANE, ADEM, and cytotoxic lesion of the corpus callosum [10–14].
The clinical course of metabolic errors and inherited metabolic disorders can include
gradually progressive or static features, followed by the emergence of an acute encephalopathic crisis, which can include lethargy, behavioral changes, or gait disturbances caused by
infections or fasting [15]. Specific therapies such as corticosteroids, immunoglobulin, freeradical scavengers, osmotic agents, immunosuppressants, plasmapheresis, and therapeutic
hypothermia have been studied extensively [16–21]. In this review, we offer an updated
summary of available data and a perspective on targeted hypothermia-based managementof pediatric acute encephalopathy.
We conducted a literature search from 1 September 2000 to 1 September 2022, using the MEDLINE/PubMed and National Institutes of Health Clinical Trials Registry(http://www.clinicaltrials.gov, accessed on 1 September 2022) electronic medical databases
for the identification of publications on the targeted hypothermia-based treatment of acuteencephalopathy. Articles were included if they were published in the English language.
We excluded conference posters. Keywords included brain hypothermia, targeted temperature management, therapeutic hypothermia, induced hypothermia, acute encephalopathy,
pediatric, children, preschool, newborn, infant, acute febrile encephalopathy, and statusepilepticus. Abstracts and full-text articles of randomized clinical trials, reviews, and otherstudy designs were considered from studies describing relevant data on pediatric acuteencephalopathy. An additional search was carried out via Google Scholar, and relevant
articles on prospective and retrospective designs and real-world data on pediatric acuteencephalopathy were considered.
2. Therapeutic Hypothermia
Hyperthermia is thought to be an independent poor prognostic factor in acute encephalopathy. Accordingly, numerous pharmacologic and nonpharmacologic strategies,
such as targeted temperature management (TTM), have been reported when general anesthesia medication fails [22–26]. Neonatal brain hypothermia therapy (BHT) is cooling of

J. Clin. Med. 2023, 12, 2095

3 of 14the head only. As brain temperature in acute encephalopathy has been reported to be
1 ◦ C–2 ◦ C higher than core temperature, children were subjected to BHT for 48 h using thewhole-body cooling system to set the body temperature at 33.5 ◦ C–35 ◦ C [23]. Since thebody surface area of the head becomes smaller as the child grows, head cooling and wholebody cooling are used together to lower the body temperature more efficiently. Treatment
for mild BHT that keeps the body temperature at 34.5 ◦ C–36 ◦ C has gained attention inrecent years [27]. Moreover, hospitals have developed a BHT strategy for treating acuteencephalitis or encephalopathy and status epilepticus in children. Regarding the long-term
effects of AESD, hypothermia therapy may be helpful in preventing the emergence ofpostencephalopathic epilepsy, thereby improving patients’ quality of life [26].
BHT is effective in neonates due to their large head surface area while adolescents
may need whole-body cooling as an effective measure. Eventually, the field of emergency
medicine advocated TTM, which is controlled at a temperature not as low as BHT. TTM
is defined as temperature control (34.5 ◦ C–37 ◦ C) with intubation and continuous useof anticonvulsants and muscle relaxants used within 24 h of onset [21]. According tonumerous case reports and retrospective investigations, the neurological outcomes ofacute encephalitis or encephalopathy can be greatly improved by focused TTM [2,21].
TTM is often used in neurocritical care to minimize secondary neurologic injury andimprove outcomes. TTM is best supported by evidence from neonatal hypoxic–ischemic
encephalopathy (HIE) and out-of-hospital cardiac arrest, although it has also been studiedin patients with ischemic stroke, traumatic brain injury, and intracranial hemorrhage [28,29].
BHT and TTM are often used synonymously in pediatric practice. However, there are key
differences in their approaches. Table 1 presents the summary of BHT and TTM. Mild BHT,
followed by TTM, may be an effective way to improve neurological outcomes in children
with HSES [27]. Although therapeutic hypothermia has been efficient, finding a solution toside effects such as bradycardia, low blood pressure, and abnormal coagulation has provendifficult [30].
Table 1. Distinguishing between BHT and TTM.
BHT

TTM

Head cooling alone for neonates
Whole-body cooling for infants and children

Whole body mild cooling

Lower body temperature by more than 2 ◦ C
The target body temperature for BHT is
32 ◦ C to 35 ◦ C

Lower body temperature by 1–2 ◦ C
TTM maintains and controls the target body temperature at36 ◦ C for an extended period of time

Generally, ventilator management is required

Ventilator management is not requiredHigher rewarming process

Relatively less duration of rewarming phase

Requires ICU support-intubation and ventilator management.
Intravenous fluids, maintenance of blood pressure, andsystemic circulatory control are required.

Can be performed in general wards

Antiepileptic drugs such as barbiturates and steroid pulse
therapy are often used in combination in severe pediatricacute encephalopathy.

For the most severe form of acute encephalopathy in children
with high-cytokine type, TTM is not sufficient for management.

BHT: Brain hypothermia; ICU: Intensive care unit; TTM: Targeted temperature management.

3. Brief History of Therapeutic Hypothermia
Since ancient times, humans have known the use of alternative medicines that soothe
inflammation by cooling injury and fever. Hypothermia was utilized medically by the
Egyptians 5000 years ago. It was first mentioned in the Edwin Smith Papyrus, an ancient
medical treatise on medicines and surgery written around 3500 B.C.E. Hippocrates, who
advocated burying injured troops in the snow, introduced the concept that cooling delayed
biological processes, and ultimately, death. Cooling the body as a therapeutic intervention became more widespread in the 17th century when physicians such as John Floyer

J. Clin. Med. 2023, 12, 2095

4 of 14(1649–1734) began experimenting more widely with the use of hot and cold water inmedicine. The use of cryoanalgesia for amputations around the 1800s led surgeons todiscover that the analgesic effects of cryoanalgesia were accompanied by a reduction inbleeding. Local head cooling for traumatic brain injury was employed in the late 1800s,
and total body cooling was documented for the first time during World War II to treat head
injuries. Clinical investigations using very deep hypothermia were started in the 1950s and1960s but discontinued due to negative outcomes soon after. In three cardiac arrest cases
treated with mild hypothermia in the 1990s following successful resuscitation, all threepatients recovered fully and without any lasting neurological damage [31,32]. After two
prospective randomized controlled trials were published in 2002 that showed significant
improvements in neurological outcomes and short- and long-term survival, therapeutic
hypothermia gained major interest [28].
4. Pathogenesis of Neuronal Damage in Hypoxic and Hypoperfused Brain Tissue
In addition to a normal environment, the brain requires optimal pH, temperature,
blood flow, and osmolarity to execute its functions. However, any small disturbances inthis complex system highly impact the functioning of the brain. One of the presumptive
etiologies in encephalopathy is impaired glucose or oxygen delivery to the brain. Encephalopathy, and eventually, coma, can occur due to a significant decrease in substancesdelivery to the brain. Hypoxia, especially hypoxia–ischemia, can permanently damage thesensitive regions of the brain, including the thalamus, hippocampus, and cerebellum. The
magnitude and irreversibility of impairment depend on the degree and duration of hypoxia
or reduced cerebral blood flow. HIE, typically triggered by severe hypotension or cardiac
arrest, is caused by the neuronal ischemic injury cascade, which involves excitatory aminoacid release, intracellular calcium influx, lipid peroxidation, and cell death [28,33,34].
The hallmark of acute hypoxic brain injury (HBI) is encephalopathy, a neurologic syndrome characterized by abnormalities in consciousness, tone, and autonomic control. HBI isa clinical condition caused by a reduction in brain blood supply and oxygenation. The brain
derives 95% of its energy from both glucose and oxygen through oxidative metabolism. HBI
is a significant cause of mortality and morbidity in children. Hypoxic–ischemic brain injury
is caused by intercellular and intracellular events that happen before, during, and after theimbalance of these substrates and their utilization in the brain. Neurons start to rapidly
deteriorate immediately after HBI, possibly as a result of a cell death process marked bynecrosis, loss of acute plasma membrane integrity, and adenosine triphosphate (ATP) depletion. In the second stage, neurons begin to degenerate within hours to days, mostly througha cascade of an active, strictly controlled intracellular process called apoptosis. ATP synthesis within cells is reduced when blood flow is stopped. As a result, energy-dependent ion
channels become dysfunctional, which adds to intracellular sodium buildup and cytotoxic
edema. Continuous ischemia causes the production of the excitatory neurotransmitter
glutamate, which stimulates calcium influx by activating N-methyl-D-aspartate (NMDA)
receptors [28,33–35]. Studies on the human fetus have reported that the NMDA receptor isexpressed by at least 22 weeks of gestation [36]. By triggering lytic enzymes, accelerating
the generation of free radicals, and compromising mitochondrial function, calcium influx
aggravates neuronal damage. Excitotoxicity ultimately results in cell death. The neuronalischemic injury cascade, which includes the release of excitatory amino acids, intracellular calcium influx, lipid peroxidation, and cell breakdown, is the most common causeof HIE. Multiple studies have shown that immediately treating severely neurologically
impaired survivors of cardiac arrest with mild hypothermia (33 ◦ C–36 ◦ C for 12–24 h) has abeneficial effect.
5. Mechanisms of Hypothermia
More than 50 years ago, evidence of the first uncontrolled cooling for resuscitation
studies was published. Briefly, in uncontrolled studies conducted in the 1950s and 1960s,
infants who were not breathing spontaneously at 5 min after birth were immersed in cold

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5 of 14water until respiration started and then allowed to spontaneously rewarm over many
hours, due to the apparent protective effects of hypothermia. In nearly 200 asphyxiatednewborns, the outcomes were reported to be superior to historical controls [37,38].
The latent or early recovery phase of HBI represents the most important window ofopportunity for intervention. Two pioneering trials in Europe and Australia translated
animal model research in therapeutic hypothermia to humans. The exact mechanisms ofhypothermic neuroprotection remain unknown. However, hypothermia is hypothesized toreduce ischemic tissue damage by affecting metabolism—with each degree Celsius below
normal, oxygen consumption falls by 7%, almost linearly. Due to numerous neuroprotective processes, TTM has been demonstrated to be useful for treating various types ofbrain traumas. These mechanisms include lowering metabolic rate to balance oxygen
supply and demand; lowering the levels of excitatory neurotransmitters, such as glutamate;preventing ATP depletion; and lowering intracellular calcium overload to prevent neuronal
apoptosis. Additionally, hypothermia suppresses free-radical toxicity, has favorable effects
on intracellular mediator systems, and reduces intracellular acidosis [39,40].
Increasing evidence suggests that hypothermia plays a role in apoptosis suppression,
especially in the developing brain. Hypothermia initiated after severe hypoxia–ischemia,
for example, reduced apoptotic cell death but not necrotic cell death, and hypothermic
neuroprotection in preclinical studies was closely associated with suppression of activatedcaspase-3. When considered collectively, these experimental data reveal that if initiatedpromptly, within approximately 6 h of hypoxic–ischemic injury, a long duration of mild tomoderate BHT could improve long-term outcomes.
Clinical hypothermia is typically categorized on a scale of 0–4: normothermia(35.0 ◦ C–37.0 ◦ C); mild hypothermia (35.0 ◦ C–32.0 ◦ C); moderate hypothermia (32 ◦ C–28 ◦ C);
severe hypothermia (below 28.0 ◦ C). The urinary bladder is heated to 34.5 ◦ C to maintainbody temperature. After 48 h of continued hypothermia, the body temperature begins
to rise at a rate of 0.5 ◦ C every 12 h. The concurrent administration of mannitol andanesthetics is applied while administering steroid pulse therapy. A flowchart of the BHT
to TTM method is shown in Figure 1. BHT is performed in three stages. The first stage
is the introduction stage, followed by the cooling stage and the rewarming stage. The
aim is to maintain the temperature of the urinary bladder at 34.5 ◦ C for 48 h. Respiration,
electrocardiogram, central venous pressure, and oxygen saturation are monitored concurrently during BHT. If necessary, a portable electroencephalogram is available, along witha scalp skin oxygen saturation device (INVOS), a bispectral index (BIS) monitor, and an
intracranial pressure monitor.

(a)Figure 1. Cont.

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Figure 1. (a) Process for mild-brain hypothermia therapy with steroid pulse therapy [24]. (b) Procedurefrom mild-brain hypothermia therapy to targeted temperature management. AESD: Acute encephalopathy with biphasic seizures and late reduced diffusion; ANE: Acute necrotizing encephalopathy.

6. Evidence of Therapeutic Hypothermia in Acute Encephalopathy
Clinical studies highlight the efficacy of BHT for pediatric acute encephalopathy. However, high-quality studies, including a large number of cases, demonstrate that the efficacy
and safety of therapeutic techniques used in BHT for pediatric acute encephalopathy are
limited. These studies have mainly focused on BHT and reported on acute encephalopathy
in adults after cardiopulmonary resuscitation associated with out-of-hospital cardiac arrest
and caused by ventricular arrhythmia and HIE in infants.
Especially in newborns and young children, hypoxic–ischemic encephalopathy causedby asphyxia is linked to high mortality and long-term neurodevelopmental impairment.
Data from 11 RCTs (N = 1505 term and late preterm infants) were compiled in a recent
Cochrane review. According to the review, TTM helped term babies who had HIE. In termneonates born with HIE, the risk of death or severe disability in the form of neurodevelopmental disability was reduced. The death rate of newborns with this condition can be
decreased using both selective head cooling and whole-body cooling techniques. Mild TH(33.5 ◦ C–34.5 ◦ C for 72 h) is used to treat term babies (35-week gestation) with hypoxic–
ischemic insult in the perinatal phase [41]. According to the results of a randomized trial(N = 168 infants), hypothermia started between 6 and 24 h after birth had a 76% chance of
reducing death or disability among term infants with HIE and a 64% chance of reducing
death or disability by at least 2% by the time they were 18–22 months old, compared withwhen no cooling techniques were used [42]. Evidence indicates lowering temperature is
the most economical intervention with better outcomes for neonates with severe perinatal
HIE. Compared with no cooling, more neonates survive morbidity-free despite the higher
cost of hypothermia intervention [43]. In several Japanese tertiary centers, therapeutic
hypothermia has been used for managing brain edema in pediatric patients with brain
injuries, including postcardiac arrest syndrome and acute encephalopathy associated withfebrile infection, which has been extrapolated from neonatal HIE and adult postcardiac
arrest syndrome.
The clinical diagnostic classification of pediatric acute encephalopathy has advanced
recently, in part because of advancements in radiological diagnosis. Many of the most severecases of pediatric acute encephalopathies, including ANE, HSES, AESD, and convulsionoverload encephalopathy, do not respond well to conventional treatment; therefore, hypothermic treatment is expected to be effective.
Based on the evidence for BHT in adults and neonates, we started using BHT inchildren to treat cytokine storm-related encephalopathy, which has status epilepticus as its
principal symptom. In addition, we used it in cases of near-drowning based on data from

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7 of 14neonatal HIE. We emphasized the management of the CNS and therapy in our treatment
plans for acute encephalopathy and status epilepticus.
Cerebral cryotherapy is likely to be useful in delaying the development of the second
phase or reducing the sequelae in AESD, where early diagnosis is challenging becauseof the biphasic course and frequently delayed treatment. In a retrospective analysis of
34 patients with AESD who were admitted over a 14-year period, therapeutic hypothermia
was started before the second phase in patients who had more significant consciousness
disturbance between 12 and 24 h following the first seizure. Catecholamine was given to
most of these patients. Multivariate analysis revealed poor outcomes that were determinedby the presence of lesions in the basal ganglia or thalamus in the MRI as well as by the Tadascore. Third, there was a high correlation between worse outcomes and 1st time cooling in
the Early-Hypo group, despite the small population and other confounding factors, but nocorrelation was seen between the outcomes and 1st time cooling or 2nd time cooling in theoverall AESD population with TTM [44].
Recently, two case reports drew attention to the use of cerebral cryotherapy followedby TTM for most severe pediatric acute encephalopathy with a good prognosis. The firstcase of HSES was reported. The second case involved a case of multiple encephalopathy
syndrome, which included multiple pediatric acute encephalopathies, such as ANE, AESD,
MERS, and acute small encephalopathy. The cryotherapy protocol used in these two cases
is shown in Figure 2. Both cases were treated with steroid pulse therapy, and both beganwith 76-h BHT, steroid pulse therapy, and gammaglobulin therapy [20,45]. TTM is thenextended. This new protocol for severe pediatric acute encephalopathy, which consists of
cerebral cryotherapy followed by TTM, has the potential to be a new treatment modality,
and we hope to see more cases in the future.

Figure 2. Brain hypothermia therapy is managed in the ICU followed by targeted temperature
management in the ICU or general ward [27]. BHT: Brain hypothermia; ICU: Intensive care unit;
TTM: Targeted temperature management. Case description: A 4-year-old patient was immediately admitted to the intensive care unit. Within 4 h of symptom onset, she received mild-brain
hypothermia therapy with a target body temperature of 35 ◦ C for 48–72 h with ICU management.
Methylprednisolone pulse, high dose immunoglobulin, and large doses of circulatory drugs wereadministered. After 72 h of brain hypothermia therapy, targeted temperature management witha target body temperature between 36 ◦ C and 37 ◦ C was continued for 96 h while weaned fromventilation. Magnetic resonance imaging results revealed no signs of acute encephalopathy. She wasdischarged without neurological sequelae 28 d after symptom onset.

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A retrospective study of children with acute encephalopathy and serum aspartate
aminotransferase levels below 90 IU/L within 6 h of onset (N = 57 children) evaluated theeffectiveness of TTM. Grade 1 in Pediatric Cerebral Performance Category Scale, representing
good clinical outcomes, was observed in 67% of the children [21]. Another retrospective
study compared the clinical course and outcome in 20 children treated with TTM (36 ◦ C) andmethylprednisolone pulse (MP) therapy (TTM/MP) with those treated with conventional
MP therapy in a secondary emergency care hospital. All children treated with TTM/MP
survived, and their body temperature dropped quickly. Some cases of acute encephalopathy
are of the so-called fulminant kind, in which DIC or shock manifests quickly after the start,
making it occasionally challenging to administer TTM. Patients of the fulminant variety
need to be taken to tertiary emergency care facilities. Secondary emergency care facilities
must carefully choose patients for TTM while considering the likelihood of evacuation to atertiary emergency facility [46]. Table 2 summarizes the evidence for TTM or BHT in acuteencephalopathy, and Table 3 summarizes the BHT protocol at our center.
Table 2. Summary of clinical studies and case reports for targeted temperature management in acuteencephalopathy [20,29,47–50].
Indication

Age (Years)

N

Goal Temp. (◦ C)

Duration of
Hypothermia, Hours

Findings

Guilliams et al.
(2013) [47]Refractory statusepilepticus

5 months–15 years

5

32–35

24–120No recurrence (100%).
One child died. Twopatients required
PICU care.

Nishiyama et al.
(2015) [21]Acuteencephalopathy
without serum
aspartateaminotransferase
elevation

6.9–14.2 years

57

34.5–36

72

Good neurologicaloutcomes (100%). PICU
not required

102 to HT
106 to control

Esophageal
temperature of 33.5
for 72 h

72 hDeath or moderate orsevere disability: 44%
with whole-bodycooling vs. 62% control.
(risk ratio, 0.72; 95% CI,
0.54 to 0.95; p = 0.01)

48–72

PCPC outcomes: Early
HT (≤12 h): 14/17(82.4%) versus late HT(>12 h): 2/10 (20%)
versus NT: 9/16 (56.3%)

72

Hypothermia treatmentof 72 h is better than
48 h for improving
oxidative conditions,
reducing NSE values,
and improving
neurological behavior

72 hHead cooling had noeffect on infants withthe most severe aEEG
changes (n = 46, 1.8;
0.49–6.4, p = 0.51), but
was beneficial to infants
with less severe aEEG
changes (n = 172, 0.42;
0.22–0.80, p = 0.009).

Reference
TTM

Shankaran et al.
(2005) [29]Moderate/severe
HIE

Neonates of at least
36 weeks

Brain Hypothermia Therapy
Kawano et al.
(2011) [48]Acute childencephalopathy
and encephalitis
treated at PICUs.

Yang et al.
(2020) [49]Moderate/severe
HIE with 1-min
Apgar score ≤ 3
and 5-min Apgar
score ≤ 5

Gluckman et al.
(2005) [50]Moderate/severeHIE

2–5 years

Neonates < 6 h

Neonates < 6 h43

33.5–35

62 to HT group30 to control group28.0–30.0(head skin Temp.);34.5 ± 0.5(body surface skin);35.5 ± 0.5(anal temp)

116 to HT group
118 to control group

Rectal temperature
maintained at 34–35

aEEG: Amplitude-integrated electroencephalography; HIE: Hypoxic Ischemic Encephalopathy; HT: Hypothermia;
NSE: Neuron-specific enolase; PICU: Pediatric intensive care unit.

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Table 3. Proposed protocol for BHT followed by targeted temperature management (Dokkyo Medical
University Hospital ICU: 2020).
Antiseizure medication treatment for status epilepticus(A) Midazolam (0.5 mg/kg) administered through 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 years: intravenous phenobarbital; between 15 and 20 mg/kg (10 min i.v.), ≥2 years: phenobarbital or fosphenytoin
22.5 mg/kg (10 min i.v.). If febrile convulsions associated with fever and Dravet syndrome cannot be ruled out, phenobarbital should be usedinstead of fosphenytoin.
(D) Sodium thiopental between 3 and 5 mg/kg (slow i.v.).
Brain hypothermia therapy
This protocol applies to infants weighing ≥7.5 kg and aged ≥6 months.
Introductory period
1. Status epilepticus/acute encephalopathy admission: ICU (request for admission), contact brainwave department or radiology(brain and chest CT).
2. Check vital signs and establish a peripheral line.
3. Establish central venous line: establish double/triple lumen catheter and arterial line.
4. Fluid infusion between 80 and 100 mL/kg/d: under whole-body management, fluid control must not be reduced to more than necessary tomaintain blood pressure and cerebral circulation. Blood pressure is evaluated using an arterial pressure monitor. Maintenance fluids comprise theprepared acetic acid and lactic acid. Vitamins are administered. When theophylline is administered, vitamin B6 is measured (light-shielding bloodcollection tube: administer vitamin B6 for theophylline-related seizures. Take care not to induce cardiac arrest by sudden administration of B6).
5. Manage blood count, electrolytes, blood sugar, albumin, and clotting value. Submit to check ferritin, soluble IL-2R (sIL-2R), β2MG, procalcitonin,
immunoglobulin, etc.
6. Mannitol 3–5 mL/kg × 4–6 times/d is administered over 1 h.
7. Harvest spinal fluid (after the first administration of mannitol). Submit to check the general spinal fluid, various cytokines (IL-6, IL-1β, andTNF-α), and tau protein. Freeze and store the remaining fluid at −80 ◦ C.
8. If possible, implement MRI (DWI/ADC-map) time-wise.
9. Intratracheal intubation (if difficult, use muscle relaxant or inhalation anesthetic).
10. Artificial ventilation: use pCO2 at 35–40 mmHg (do not over-ventilate). Keep PEEP slightly low considering brain hypertension. Raise head by
10◦ . If brain hypertension occurs, request placement of intracerebral pressure (ICP) monitor by a neurosurgeon.
11. Steroid pulse therapy: use methylprednisolone 30 mg/kg for >2 h for 3 d, during which heparin or fragmin therapy is continued ≥APTT 1.5.
12. Administer famotidine 0.5 mg/kg twice/day or omeprazole (15 years and older 20 mg twice/day).
13. Brain hypothermia therapy: use the whole-body blanket-cooling method to induce target body temperature (direct intestine or bladdertemperature of 34.0 ◦ C–35.0 ◦ C or 35.5 ◦ C) within 6 h of onset. If necessary, cool the head or wash the stomach with normal saline while taking care
not to cause electrolyte abnormalities or use chilled fluid infusion. Brain hypothermia is managed in the ICU followed by TTM in the ICU or
intensively manageable general ward. TTM of maintaining brain temperature between 36 ◦ C and 37 ◦ C using bladder temperature as an indicator,
with a high correlation.
14. Antiseizure medication: use sodium thiopental, 5–10 mg/kg/h (if this cannot be used, consider midazolam, 0.3–0.9 mg/kg/h).
15. Mitochondrial rescue therapy (MRT): use coenzyme Q10 3–5 mg/kg/day, Vitamin B2 5 mg/kg/day, Vitamin C 50 mg/kg/day, Vitamin H
0.5 mg/kg/day, Vitamin B1 10 mg/kg/day, Vitamin B6 20–50 mg/kg/day, Vitamin B12 0.03–0.05 mg/kg/day, Vitamin E 10 mg/kg/day, andCarnitine 50–100 mg/kg/day. The duration of treatment should be determined by the clinical course. It is usually 2 weeks or more.
16. Dexstromethorphan therapy: use 2 mg/kg for 5 days for prevention of biphasic encephalopathy after febrile status convulsive. Start within 6 hof onset of convulsion.
17. Sedation depth should be confirmed by portable electroencephalograph or paperless electroencephalograph (Makin2) as reaching suppression
burst within 6 h of beginning therapy.
Cooling period
18. Maintain the target temperature for 48 h (or a maximum of 72 h) in the ICU or general ward. Confirm BIS value at suppression burst (aim for 40
or below) and adjust the sodium thiopental dose administered based on BIS value as appropriate.
Cases achieving positive sedation depth should have their sodium thiopental dose reduced prior to rewarming at BIS values between 60 and 70, andat a body temperature of 35.0 ◦ C.
[Caution] If spikes remain with suppression bursts, consider complete suppression (pupils will constrict to mydriasis, and response to light is lostwith a BIS value of 20 or lower).
19. Use INVOSTM at an appropriate time to check oxygen saturation at the left and right front scalp and to evaluate brain circulation.
20. Blood pressure maintenance: use an appropriate dose of dopamine hydrochloride (5 µg/kg/min = 0.3 mg/kg/h = 0.015 mL/kg/h) and manage
electrolyte abnormalities and blood glucose. Heart rate will fall to bradycardia with falling body temperature.
21. Administer antibacterial as appropriate. In applicable conditions, cerebroprotective edaravone, sivelestat Na as a neutrophil elastase inhibitor,
and acyclovir are administered.
Rewarming period
22. Rewarming is performed at a rate of 0.5 ◦ C/12 h. Care should be taken to avoid pneumonia in line with increased sputum secretions. Aim toremove the patient from artificial respiration between days 5 and 7. For cases in which laryngitis is likely, intravenous dexamethasone or
epinephrine should be administered prior to the removal of the tube.
23. For cases in which critical complications are envisaged, TRH therapy should be initiated at an early stage.
24 Include rehabilitation, aiming to discharge the patient one month after onset.
25. Prior to discharge, evaluate brain waves, implement neuroradiological images or nuclear medicine tests, and assess development. Where
necessary, antiseizure mediation should be periodically administered for preventative purposes.

Data from clinical trials in high-income countries suggest that using induced hypothermia for moderate or severe neonatal encephalopathy reduces death or disability at
18 months [51]. When not managed properly, however, TTM can be associated with nega-

J. Clin. Med. 2023, 12, 2095

10 of 14

tive effects and unfavorable outcomes. In pediatric patients with head injury or postcardiac
arrest, hypotension has been linked to therapeutic hypothermia, and thrombocytopenia
has been linked to therapeutic hypothermia in adult patients with head injuries and infants
with HIE. Among children with mild-to-severe neonatal encephalopathy, TTM was independently associated with decreased odds of abnormal motor (OR: 0.15, 95% CI: 0.06–0.40,
p < 0.001) and cognitive (OR: 0.11, 95% CI: 0.04–0.33, p < 0.001) outcomes even after adjusting for propensity [52]. After neonatal encephalopathy, therapeutic hypothermia isassociated with lower rates of brain injury and worse 30-month outcomes. Therapeutic
hypothermia has no effect on the predictive accuracy of MRI in the first week of life. Normal MRI continues to be reassuring for a normal 30-month outcome following therapeutic
hypothermia [53].
7. Gaps and Future Directions
In low- and middle-income countries, therapeutic hypothermia had no effect on the
combined outcome of death or disability 18 months after neonatal encephalopathy, but it
significantly increased death alone. Even when tertiary neonatal critical care facilities areavailable, therapeutic hypothermia should not be administered as a treatment for neonatal
encephalopathy in low- and middle-income nations [51]. Although therapeutic hypothermia for neonatal encephalopathy reduces neurologic impairment and cerebral palsy, its
impact on neonatal, infantile, and childhood mortality remains unknown according toa recent meta-analysis [52]. The environment in which it is executed has an impact on
the consequences. Trials of low(er) quality overstated the potential benefit of therapeutic
hypothermia. Whole-body management at the PICU level is necessary for BHT. Steroid
pulse therapy, globulin therapy, and intravenous therapy of various antiseizure drugs
are frequently used in conjunction with BHT in some cases (25). To confirm the clinicalresults of this therapy, it is necessary to evaluate the clinical course of treatment by dividing
the cases into two groups based on treatment received as follows: (1) receiving BHT and(2) receiving BHT with concomitant medicines. The number of studies on this topic islimited. However, informed consent is a deciding element in BHT research.
During acute encephalopathy, cytokine release is triggered by various factors, including infection, trauma, and other insults to the brain. The excessive release of cytokines
leads to an inflammatory response, which can result in brain damage and even death [54].
The rationale for using TTM for acute encephalopathy is to reduce cytokine-mediatedinflammation that may be exacerbated by fever and sepsis. TTM is believed to reduce
cytokine-mediated inflammation through several mechanisms. One of the primary ways
TTM works is by reducing the metabolic rate of cells, which slows down the release ofcytokines. The reduced metabolic rate also leads to a decrease in the production of reactive
oxygen species, which are known to cause oxidative stress and contribute to inflammation. TTM has also been shown to improve blood flow to the brain, which helps reduce
inflammation by increasing the delivery of oxygen and nutrients to brain cells. TTM also
has neuroprotective effects, which can help prevent further damage to the brain [55,56].
In addition, the antiepileptic effect of TTM is based on various changes at the molecularlevel. Because TTM activates multiple anticonvulsant and neuroprotective mechanisms
in the pathophysiology of acute encephalitis and refractory status epilepticus, it has thepotential to impact seizure control and neuroprotection in the setting of refractory statusepilepticus. Most studies on TTM for refractory status epilepticus have focused on animalmodels, and few clinical studies exist [57,58]. In addition, TTM may contribute to seizure
control. However, in most case studies, the patients received a combination of intravenous
anesthetic agents and TTM [47]; thus, the seizure response reported may reflect the combination of therapies. The benefits of TTM for refractory status epilepticus may be linked tothe etiology of the seizure, and further large-scale studies are needed to evaluate refractorystatus epilepticus from various causes to determine which groups would benefit from
TTM. TTM tends to be used in mild and moderate encephalopathies to avoid the risk of
BHT treatment. However, it is not certain that the most severe acute encephalopathies can

J. Clin. Med. 2023, 12, 2095

11 of 14be successfully treated with TTM alone. BHT is associated with complications, such as
arrhythmia, coagulopathy, electrolyte abnormalities, increased infection rates, and venous
thrombosis; however, it is possible to successfully use or combine BHT and TTM in different
cases to achieve a more ideal treatment for pediatric acute encephalopathies.
8. Conclusions
The targeted temperature for managing acute encephalopathy depends on the underlying cause of the condition and the severity of the symptoms. The use of targeted
temperature management for acute encephalopathy should be individualized to each patient’s specific needs and medical history and should only be applied under the guidanceof a qualified healthcare provider. We hope to establish a more ideal systemic managementof pediatric acute encephalopathy by using BHT and TTM in different or combined cases.
Author Contributions: The following authors were involved in the preparation of this paper, conceptualization, methodology, writing—original draft preparation and writing—review and editing
G.I.; supervision, Y.F., J.K., K.W., K.O. and S.Y. All authors have read and agreed to the publishedversion of the manuscript.
Funding: This research did not receive any specific grant from funding agencies in the public,commercial, or not-for-profit sectors.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors would like to thank the staff of the Department of Pediatrics andICU of Dokkyo Medical University, as well as many pediatric patients and their guardians, for theircooperation in the treatment of pediatric acute encephalopathy. The authors would also like to thankSreeHarsha Bantu for medical writing assistance and Raghuraj Puthige for editorial assistance from
Enago LifeSciences, India in accordance with good publication practices (GPP3) guidelines.
Conflicts of Interest: The authors declare no conflict of interest.

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