Seminars in Fetal & Neonatal Medicine 20 (2015) 66e71

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Seminars in Fetal & Neonatal Medicine

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Review

Who should we cool after perinatal asphyxia?

Marianne Thoresen a, b, *
a
Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
b
Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, UK

s u m m a r y
Keywords: Three ongoing challenges have arisen after the introduction of therapeutic hypothermia (TH) as standard
Hypoxiceischemic encephalopathy of care for term newborns with moderate or severe perinatal asphyxia: (i) to ensure that the correct
Therapeutic hypothermia
group of infants are cooled; (ii) to optimize the delivery of TH and intensive care in relation to the
Inclusion criteria
Follow-up
severity of the encephalopathy; (iii) to systematically follow up the long-term efcacy of TH using
Human comparable outcome data between centers and countries. This review addresses the entry criteria for TH,
Clinical trial and discusses potential issues regarding patient selection, and management of TH: cooling mild, mod-
erate, and very severe perinatal asphyxia, cooling longer or deeper, and/or starting with a greater delay.
This includes cooling of patients outside of standard trial entry criteria, such as after postnatal collapse,
premature infants, those with infection, and infants with metabolic, chromosomal or surgical diagnoses
in addition to perinatal asphyxia.
2015 Published by Elsevier Ltd.

1. Introduction
In 2010, the International Liaison Committee on Resuscitation
(ILCOR) published guidelines [1] that term-born infants with signs
of moderate or severe perinatal asphyxia should be offered thera-
peutic hypothermia (TH). Many countries, including the UK, also
published similar national recommendations; the National Insti-
tute for Health and Clinical Excellence (NICE) [2], and the British
Association of Perinatal Medicine (BAPM) [3]. All western countries
now have TH as standard of care after moderate and severe
perinatal asphyxia. Many centres had introduced this practice
already in 2007 when the UK lead TOBY trial had nished
recruiting. These recommendations on how to administer TH, and
to whom, were based on a large number of preclinical studies, pilot
[1,4e7] and smaller clinical studies [8], in addition to the rst three
large trials: CoolCap, NICHD and TOBY [9e11].
Before discussing who should we cool?, it is important to
dene who did we cool? in the above studies, which provided the
scientic basis of TH becoming the standard of care. Importantly, it
is unknown whether cooling would have been (or will be) effective
in infants who did not fulll those trial entry criteria.
* Address: Department of Physiology, Institute of Basic Medical Sciences,
University of Oslo, Oslo, Norway. Tel.: 47 22851217/1568; fax: 47 22851568.
E-mail address: marianne.thoresen@medisin.uio.no.
The researchers behind the rst TH trial, the CoolCap trial,
developed a 72 h treatment protocol [6], which was further tested
for feasibility and safety in two studies [12,13]. Based on animal
experiments from a range of species at human term equivalent age
[postnatal day 7 for rats, day 0 for pigs, and near-term (117e124
days of gestation) for fetal sheep], the optimal temperature, dura-
tion, and time window of cooling were dened to achieve long-
term neuroprotection [14].
This three-day protocol has, with minor changes, been used
since 2010 in the developed world, as part of the ILCOR guidelines.
In encephalopathic infants, cooling should start within 5.5e6 h of
birth, core temperature should be kept at 34.5
C (CoolCap) or
33.5
C (NICHD and TOBY), and cooling should last 72 h, followed by
rewarming at a rate of 0.5
C/h. The CoolCap trial used a cooling cap
combined with moderate body hypothermia to a rectal tempera-
ture (Trec) of 34.5
C [9]. Seetha Shankaran then led the rst whole-
body cooling (WBC) trial (NICHD) using a cooling blanket, with a
target oesophageal temperature of 33.5
C [10]. Later, the TOBY trial
led by Denis Azzopardi also applied WBC [11], which since 2007 has
become the preferred cooling method. There is no evidence that
either method is better. However, servo-controlled WBC gives
stable temperatures, and is less labor-intensive to apply. The entry
criteria for the rst six trials to select infants with encephalopathy
of hypoxicischemic origin are presented in Table 1. One important
difference between trials is whether (amplitude-integrated) elec-
troencephalogram (aEEG)/EEG was one of the entry criteria used to
document how the brain is affected, and the severity of the insult.

http://dx.doi.org/10.1016/j.siny.2015.01.002
1744-165X/ 2015 Published by Elsevier Ltd.
 M. Thoresen / Seminars in Fetal & Neonatal Medicine 20 (2015) 66e71
The NICHD trial, which do not use aEEG, had the most stringent
denition of abnormal neurology to ensure that the infants were
encephalopathic. All three trials aimed to recruit infants with
moderate or severe perinatal asphyxia, and excluded those with
mild perinatal asphyxia (classied as SARNAT grade 1 or a normal
aEEG pattern), as these infants were thought to have good outcome
with standard care. Those recruited using aEEG also classied the
severity of the depression of the aEEG background activity between
moderate and severe.
A narrowly dened patient group gives the best chance of
detecting a treatment effect if there is one, and thus there were
numerous exclusion criteria as listed in Table 1. When the rst three
trials (comprising nearly 800 patients) were analysed together, the
number needed to treat (NNT) for the primary outcome (death or
disability) and secondary outcome (the number surviving with
normal function) was nine and eight, respectively. In the six trials
listed in Table 1, only CoolCap reported any patients (3%) that had
mild encephalopathy at entry (they may have had subclinical sei-
zures). The other trials did not report any with mild
encephalopathy.
Recently, long-term follow-up from the rst three trials at age
6e8 years has been published [15e17]. The TOBY trial was the only
study large enough to have power to conrm that 72 h TH, starting
within 6 h of birth, offered long-term neurological protection [17],
with an NNT of eight. This number gives great scope for improving
outcome. At 18 months, 50% of cooled infants had poor outcome
dened as death or severe disability, compared to 66% in NT infants
[18]. In addition to investigating additional treatment strategies,
major emphasis should be put on investigating whether we are
using the optimal TH treatment protocol. Uniform follow-up with
comparable methods (ideally the same) is necessary, and here lies a
major responsibility at national and international levels. Specif-
ically, it seems to be easier to obtain funding for treatment than for
follow-up.
Table 1 shows the entry criteria and outcome in six different
trials. Note that three trials did not use aEEG or EEG (Criterion C) for
entry only Criteria A and B. All doctors who recruited patients for
the NICHD trial were formally trained and certied in assessing
neurology.
Unfortunately, the patients who did not meet the entry criteria
in any of the large randomized controlled trials (RCTs) were not
followed-up, so we missed the opportunity to study the outcome of
those screened but not treated. This question could still be
answered if large centers followed up, and reported, those screened
but not cooled. There is evidence that mild derangements at birth,
such as Apgar scores <7 at 1 min, reduce IQ by 8 points at 18 years
of age [19], and that grade I encephalopathy survivors have worse
behavioural outcomes at 10 years of age than matched children
with no encephalopathy [20]. However, we do not know whether it
might also be harmful to electively intubate, ventilate, sedate and
cool infants for three days who are not encephalopathic (or mildly
encephalopathic) after birth. Recent observational studies of cooled
infants have seen outcomes that are more favorable than those
presented in the RCTs (<50% poor outcome in the cooled group)
[21e23]. It is possible that infants currently recruited have milder
encephalopathy than those in the original trials. Overall mortality
in published trials (Table 1) is also likely to be dependent on local
practices for redirecting care, and may not purely represent the
effectiveness of TH.
2. Comparing current with previous outcome data
All large trials published before 2010 used death and disability,
assessed by Bayley II and the Gross Motor Function Classication
System (GMFCS) at age 18 months, as primary outcome. Since 2006,
67
Bayley III, a further-developed version of the Bayley examination,
has been used. On examining 61 cooled infants with both tests, we
found Bayley III scores to be higher than Bayley II by 10e15 points
(one standard deviation 15 points), which will result in better
outcome if reporting uncorrected Bayley III results compared with
Bayley II [24].
3. Broader entry criteria for cooling
We have expanded our local entry criteria for cooling since
December 1st, 2006. Using prospective data collected over a six-
year period in our regional cooling centre, we compared compli-
cations and outcome between infants who were cooled but who
did not fulll the standard inclusion and exclusion criteria as set out
in the CoolCap/TOBY protocol (n 36) with 129 infants who did
fulll the standard entry criteria (Table 2) [25]. The six subgroups
cooled outside of standard entry criteria were infants who started
cooling later than 6 h of age, moderately preterm infants (34e35
weeks of gestation), infants with postnatal collapse, major cranial
hemorrhage, congenital cardiac disease, and surgical conditions.
For each group, clinical details and outcome are presented. When
comparing outcome between the 36 infants included outside trial
criteria with those 129 that met traditional trial entry criteria, poor
outcome was 36 vs 35%. One group stands out with worse outcome:
ve infants with major hemorrhage, of which four had a subgaleal
hemorrhage, and one a large intraventricular hemorrhage during
rewarming. Two died, and two had poor developmental outcome.
The fth had a very mild diplegia, with normal cognition. Our local
advice is now not to cool infants with cranial bleeds until hemor-
rhage and clotting are under control, and then apply milder TH, e.g.
Trec 35
C. Currently, there are no experimental data behind this
advice other than our own clinical experience.
Another much-discussed subgroup is that of infants with post-
natal collapse. We cooled 10 such infants who fullled the A (except
Apgar), B, and C entry criteria after the collapse [25]. They were a
sick group of patients (Table 2). Fifty percent were hypoglycemic,
90% needed inotropic support, and 90% had seizures. One infant
had a metabolic disorder (very long-chain acyl-CoA dehydrogenase
deciency) diagnosed after rewarming, and was developmentally
within the normal range. Fortunately, cooling is likely to reduce the
levels of toxic metabolites [26]. Of the subgroup with postnatal
collapse, none died, and 38% had poor outcome. We continue to
assess asphyxiated infants for TH if they do not fulll the standard
criteria on an individual basis. Parents are informed, and partici-
pation requested on the basis that infants are treated outside
standard criteria. We have not had infants with a known chromo-
somal diagnosis when starting cooling, though one patient was
later diagnosed with a chromosomal deletion. Another child who
fullled criteria A and B was not cooled, as the aEEG was normal. He
was diagnosed with the neonatal form of myotonic dystrophy at a
few days of age, with the mother and grandmother having the same
diagnosis.
Table 2 (data summarized from Smit et al. [25]) shows the de-
mographic data and outcome from 129 infants recruited as advised
in the CoolCap/TOBY protocols, and 36 infants recruited outside
these criteria. Data from the 36 infants were grouped according to
those criteria that were not implemented.
4. Effective time window for TH
The original decision for the CoolCap trial to start within 5.5 h of
age was based on Gunn's thorough animal experiments in fetal
sheep [27]. This important time window was then found to be the
same as in a very different preclinical model, the seven-day-old rat
[28]. Experimentally, the effectiveness of TH improves with an
Table 1

68
Entry criteria for the rst six trials to select infants with encephalopathy of hypoxicischemic origin.

Study criteria CoolCap (n 235) TOBY (n 325) NICHD trial (n 208) Eicher trial (n 67) neo.nNeur (n 129) ICE (542 screened)
(23 sites) (43 sites) (31 sites) (6 sites) (24 sites) (n 204)
(28 sites)

Gestation (weeks) 36 36 36 35 36 35

Start cooling (hours) 5.5 6.0 6.0 6.0 h or after postnatal insult 6.0 6.0
A criteria
Metabolic 1 out of 4 1 out of 4 1 out of 4 1 out of 5 1 out of 4 2 out of 4
Apgar at 10 min 5 5 5 5 5 5
pH <7.00 <7.00 <7.00 <7.00/7.1 (initial infant gas) <7.00 <7.00
Base excess (mmol/L) 16 16 16 13 16 12
Ventilated or Yes Yes Yes Yes at 5 min Yes Yes
resuscitated at
10 min
Other Heart rate <80 bpm for 15 min
postnatal HI event with oxygen
desaturation <70% or arterial

M. Thoresen / Seminars in Fetal & Neonatal Medicine 20 (2015) 66e71

B criteria
Neurology Depressed consciousness
AND 1 out of 3:
Hypotonia; Abnormal
reexes (including
oculomotor or pupillary
abnormalities); Abnormal
suck
AND
C criteria
Seizures or aEEG Clinical seizures or
abnormal aEEG
Poor outcome HT 55%
Poor outcome NT 66%
Mortality % HT 33%
Mortality % NT 38%
% infants included 3%
with Grade I
encephalopathy or
normal aEEG (if
aEEG)
Outcome assessment At 18 months:
methods and age MDI Bayley II <70 and/or
GMFCS 3e5, and or severe
visual or hearing loss
Depressed consciousness 3 out of 6: Depressed
AND 1 out of 3: consciousness;
Hypotonia; Tone;
Abnormal reexes Autonomic reexes; Autonomic dysfunction;
(including oculomotor or Primitive reexes; Reexes;
pupillary abnormalities); Activity;
Abnormal suck Posture
AND
Clinical seizures or Clinical seizures, no aEEG
abnormal aEEG
48% 49%
53% 63%
26% 24%
27% 37%
None reported None reported
At 18 months: At 18e22 months:
MDI Bayley II <70 and/or Severe disability:
GMFCS 3e5, and or severe MDI Bayley II <70 and/or
visual or hearing loss GMFCS 3e5, and/or severe
visual or hearing loss
Moderate disability:
MDI Bayley II 70e84, and/
or GMFCS 2, and or hearing
impairment with no
amplication or a neurodevelopmental tests of motor
persistent seizure disorder
oxygen tension <35 mmHg for
20 min with evidence of ischemia
(chest compressions, hypotension,
hemorrhage)
2 out of 6:
Consciousness;
Tone;
Hypotonia;
Abnormal reexes (incl
Posture;
Seizures
Clinical seizures, no aEEG
52%
84%
31%
42%
None reported
At 12 months using the BSIDII,
Cognitive Adaptive Test/Clinical
Linguistic and Auditory Milestone
Scale (CAT/CLAMS) or Vineland
examinations. Severely abnormal
scores were dened as >2 SD from
mean, moderately abnormal as >1
and 2 SD, and mildly abnormal to
normal as 1 SD on
function (Bayley PDI, Vineland
gross motor) and cognitive function
(Bayley MDI/CAT/CLAMS) in both
groups
Encephalopathy with lethargy,
stupor or coma AND at least 1
out of 4:
e117)
Dened as two or more of:
oculomotor or pupillary
abnormalities);
Abnormal suck;
Clinical seizures AND
Clinical seizures or abnormal
standard EEG or aEEG
49%
83%
38
57
None reported
At 18e21 months
Severe disability:
GMFCS 3e5, a development
quotient of <2 SD, severe
bilateral cortical visual decit,
or any combination of the
above
Moderate or severe Sarnat
encephalopathy modied by
Finer NN, J Pediatr 1981;98:112
Alteration of consciousness;
Global hypotonia or
hypertonia;
Abnormal Moro reex;
Grasp and suck reexes
Seizures or aEEG not included
in entry criteria
51%
66%
25%
38%
None reported
At 24 months using both Bayley
II and III with <2 SD in
different domains as poor
outcome or GMFCS 3e5, and or
severe visual or hearing loss

aEEG, amplitude-integrated electroencephalogram; HI, hypoxicischemic; HT, hypothermia; NT, normothermia; MDI, Mental Developmental Index; GMCSF, Gross Motor Function Classication System (a 5 level classication
system); BSIDII, Bayley Scales of Infant Development II; PDI, Psychomotor Development Index.
 M. Thoresen / Seminars in Fetal & Neonatal Medicine 20 (2015) 66e71 69

Table 2
Comparison of outcomes for cooled infants who did and did not fulll the standard inclusion and exclusion criteria in the CoolCap/TOBY protocol. Modied from [25].

Infants not fullling the entry criteria Sub-categories P-value

combined comparing
last 2
Cooled >6 h Postnatal Preterm Major cranial Cardiac Surgical Entry criteria Entry criteria
columns
(n 11) collapse <36/40 hemorrhage diagnosis diagnosis not fullled fullled
(n 10) (n 6) (n 5) (n 2) (n 2) (n 36) (n 129)

Gestational age in weeks, mean (SD) 405 (06) 396 (13) 346 (05) 386 (12) 384 (05) 391 (02) 39 (22) 396 (14) NS
10 min Apgar score, median (IQR) 8 (7e9) 9 (7e10) 6 (4e10) 8 (5e9) 7 5 8 (5e9) 6 (4e8) 0.002
Worst pH in rst postnatal hour or rst 6.92 (0.17) 7 (0.3) 6.93 (0.17) 7.02 (0.22) 6.86 (0.12) 6.95 (0.06) 6.99 (0.2) 6.96 (0.7) NS
hour post collapse, mean (SD)
Worst BE in rst postnatal hour or rst 15.7 (5.6) 16.1 (6.4) 19.2 (7.5) 13.3 (7.8) 18.9 (0.7) 12.6 (6.3) 15.6 (6.3) 15.5 (6.3) NS
hour post collapse mEq/L, mean (SD)
Persistent pulmonary hypertension, n (%) 2 (18) 0 1 (17) 0 0 1 (50) 4 (11) 13 (10) NS
Hypotension requiring inotropic 6 (55) 9 (90) 4 (67) 4 (80) 2 (100) 2 (100) 27 (75) 86 (67) NS
support, n (%)
Seizures treated with anticonvulsants, 5 (45) 9 (90) 3 (50) 5 (100) 1 (50) 1 (50) 24 (67) 88 (68) NS
n (%)
First hour hypoglycemia <46.8 mg/L 2 (18) 5 (50) 2 (33) 3 (60) 1 (50) 1 (50) 14 (39) 36 (28) NS
(<2.6 mmol/L) n(%)
Coagulopathy, n (%) 0 5 (50) 3 (50) 5 (100) 1 (50) 0 14 (39) 37 (29) NS
Thrombocytopenia, n (%) 0 2 (20) 3 (50) 2 (40) 1 (50) 1 (50) 9 (25) 24 (19) NS
Culture-proven sepsis, n (%) 1 (9) 1 (10) 0 0 0 1 (50) 3 (8) 3 (2) NS
Length of stay on NICU for survivors, 12 (9e16) 13 (10e17) 15 (9e36) 34 (14e68) 17 38 12 (10e19) 11 (9e13) 0.019
median (IQR)
Died, n (%) 1 0 0 2 1 0 4 (11) 20 (16)
MDI <70, PDI 70 0 2 0 1 0 0 3 4
PDI <70, MDI 70 1 1 0 1 0 1 4 9
MDI and PDI <70 1 0 1 0 0 0 2 9
% poor outcome (death or MDI 31 38 25 80 50 50 13 (36) 45 (35)
and/or PDI <70)

SD, standard deviation; NS, non-signicant; IQR, interquartile range; BE, base excess; NICU, neonatal intensive care unit; MDI, Mental Developmental Index; PDI, Psychomotor
Development Index; BSIDII, Bayley Scales of Infant Development II.

earlier start, and this was supported in our observational cohort
study with regard to motor outcome, but not cognition [29]. How-
ever, there is no study with large enough patient numbers and a late
cooling start to suggest whether late cooling is effective or not. We
are awaiting results from a US trial that has recruited with the aim of
answering this question (no cooling versus late cooling, starting
6e24 h after birth) [30]. There is no evidence clinically or experi-
mentally that TH is harmful, at least not until 9 h, after which there is
no effect at all [28,31]. After very severe insults, starting cooling late
at 12 h increased injury in the rat model [28]. The advice therefore is
still the same: start cooling within 6 h, or earlier if possible.
and possible benet from very cautious, incremental pilot clinical
studies, such as that from the late Tania Gunn [6,33] and others
[12,13,34].
The recent report from Shankaran et al. [Optimizing (Longer,
Deeper) Cooling for Neonatal HypoxiceIschemic Encephalopathy
trial] was stopped after 50% recruitment, and strongly suggests that
much longer (ve days) or deeper (to 32
C) cooling than current
clinical protocols for neonatal encephalopathy is at least futile, and
may be harmful [32]. This conclusion was based on short-term
survival.

5. Duration of hypothermia
The current protocol of 72 h cooling is based on a foundation of
solid mechanistic and empirical studies. Large animal studies
showed that the secondary phase of seizures and edema, and the
bulk cell death, resolve over ~48e72 h after hypoxiaeischemia.
Consistent with this, cooling for the same broad period improved
outcomes without rebound deterioration after rewarming [4,5].
Until the recent study by Shankaran et al. [32], no other duration of
TH had been trialed in term newborns. Alistar Gunn and collabo-
rators showed in fetal sheep that 5 days of hypothermia increased
injury as compared to 3 days [6].
6. Depth of hypothermia
In term piglets, WBC from 38.5 to 35
C (i.e. a 3.5
C reduction in
core temperature) prevented secondary energy failure and reduced
neuronal loss [4]. Brain cooling in near-term fetal sheep was
associated with a steep, sigmoidal relationship between brain
cooling and protection, with no further benet at brain tempera-
tures below ~34
C (4
C reduction in core temperature). These
preclinical studies in turn were supported by the apparent safety
7. Cooling less
Therapeutic hypothermia is also standard of care in adults after
Out of Hospital Cardiac Arrest (published by ILCOR in 2003). The
adult cooling protocols have advocated cooling to Trec 33.0
C for
12e36 h in different trials [35]. This was recently questioned by the
Targeted Temperature Management (TTM) trial, which randomized
939 patients to 28 h of hypothermia at 33
C, or controlled normo-
thermia at 36
C, followed by 36 h of controlled normothermia (total
intervention time of 72 h including rewarming) [36]. This study
found no difference in neurological outcome (at six months) be-
tween the two groups. The authors suggested that, in this setting at
least, prevention of hyperthermia was the main neuroprotective
factor achieved by active cooling. Cooling to core temperatures
above 33.5
C after neonatal asphyxia was trialed in the CoolCap
study, where a target Trec of 34.5
C was used. However, there has
been no study in which selective head cooling (SHC) and WBC (or
34.5 vs 33.5
C) have been compared head to head clinically. In a
study using newborn piglets, SHC and WBC were compared to
normothermia, and there was no difference in degree of, or distri-
bution of, brain injury between the two cooling methods [37]. A
recent experimental series in newborn pigs combined 48 h of SHC
and very mild body cooling (1.5
C reduction in core temperature
70 M. Thoresen / Seminars in Fetal & Neonatal Medicine 20 (2015) 66e71
from 38.5 to 37.0
C). We found, to our surprise, no neuroprotection
from TH in this study albeit the deep brain was 3
C colder than core,
and the duration of treatment was long for piglets; 48 h as
compared to the usual 24 h. More experimental work is needed to
guide the best possible human trial on minimal hypothermia [38].
8. Cooling after very severe insults
The CoolCap trial suggested, based on recruiting 30% of the
patients with a very severely abnormal aEEG, that these patients
received less benet from cooling. When all trials are analysed
together [39], however, there is a suggestion that there might be
some effect of hypothermia in the severe group. Experimental
studies have also addressed this question. Sabir et al. developed a
severe version of the RiceVannucci neonatal brain injury rat
model [28]. Five hours of post-insult hypothermia gives 40% neu-
roprotection in the standard injury model. In the severe model,
however, there was no protection of immediate or delayed hypo-
thermia. It is natural to ask whether deeper hypothermia might be
protective against a severe insult. Temperatures as low as 18
C were
also tried, and none was protective. In fact, 5 h at 18
C slightly
increased the injury in the severe model [40]. Longer cooling for
10 h instead of 5 h was also tried in the same model, with no
improved protection. There is experimentally no suggestion that
cooling longer or deeper, even if starting immediately, protects
against severe insults.
9. Cooling premature infants
We cooled 11 infants <36 weeks of gestation and appropriate for
age, who had clear signs of moderate or severe perinatal asphyxia.
They responded well to the hypothermia treatment with no com-
plications and had good outcomes (Table 2). Before outcome data
from a properly designed RCT of cooling premature babies is
available, we deem the decision whether to cool infants of 34 or 35
weeks of gestation (but not younger) to be for consultants after
discussion with the parents. In a different setting, very premature
infants with necrotizing enterocolitis needing surgery are being
randomized between surgery at normothermia or hypothermia
followed by normothermia or hypothermia for 48 h [41], the hy-
pothesis being that hypothermia reduces inammation and im-
proves outcome.
10. Cooling infants that are small for gestational age
In the CoolCap and TOBY trials, being <1800 g was an exclusion
criteria. In a secondary analysis of the CoolCap data, it was shown
that there was signicant interaction between treatment outcome
and weight, which was better for larger children (25th centile)
[42]. Current TH protocols sometimes exclude small-for-date in-
fants. The data suggest that TH is less effective in small for gesta-
tional age infants. However, there is also no evidence that TH is
harmful.
11. Cooling infants with infections
Any evidence of infection was an exclusion criterion in the initial
trials. The occurrence of later infection documented as positive
blood cultures was similar in the hypothermia and normothermia
arms, and varied from 3% to 12%. The numbers are too low to test
whether infected infants were harmed, or had benet from TH.
Hypothermia delays the C-reactive protein (CRP) response in in-
fants with positive risk factors for infection [43]. If deciding to start
antibiotic therapy in response to a CRP increase, this might delay
the start of appropriate treatment. In adults, pilot studies suggested
that hypothermia reduced inammatory responses, and it was
suggested that hypothermia might protect the brain during men-
ingitis. An adult clinical trial showed the opposite, however, with
increased mortality in the cooled group (48 h at 32e34
C) in adult
patients with bacterial meningitis [44]. A recent case report also
describes an asphyxiated term newborn with GBS septicemia who
was cooled. There was impaired hemostasis prior to TH, and the
outcome was poor [45].
A current (yet to be formally tested) hypothesis also suggests
that infants in poorer countries will respond less favorably to
cooling, due to a larger infection burden. A recent experimental
study sensitizing neonatal rats with lipopolysaccharide (LPS) before
a mild hypoxicischemic insult abolished the neuroprotective role
of TH [46]. Evidence is lacking with regard to the interaction be-
tween infection and TH in asphyxiated infants. Currently there is no
randomized evidence on which to base the exclusion of infants
with signs of infection. On the other hand, caution, and clinical
judgement, for individual patients should apply. This area needs
further experimental studies, as well as collection of data from
infants who have been cooled.
12. Conclusion
The rst cooling protocol for term infants with perinatal
asphyxia was developed based on robust preclinical studies using
different species. Now, after 17 years, there is no major change to
this protocol: start TH within 6 h of age, cool to 33.5
C for 72 h, and
rewarm for 4 h. It is difcult to document encephalopathy
without using aEEG/EEG or the strict neurological criteria devel-
oped by Shankaran [10]. We do not know whether cooling non-
encephalopathic infants may be harmful. Cooling deeper (to
32.0
C) and/or longer (5 days) in a recent trial, which was stopped
prematurely due to lack of efcacy, did not suggest any benet [32].
There is also little experimental evidence that TH in any form
protects against very severe insults. An observational study sug-
gests that cooling outside the standard entry criteria (infants with
postnatal collapse, age >6 h, gestational age 34e35 weeks) may be
safe and benecial. However, infants with ongoing hemorrhage did
not do well. There were too few infants with severe infection to give
any advice other than general caution based on adult data. The
original neonatal protocols have proven robust and valid. Further-
more, with parental approval, asphyxiated infants with additional
diagnosis may benet from TH.
Practice points
 The main entry criteria and cooling protocol have not
been changed; start TH within 6 h of age and cool to
33.5
C rectal temperature for 72 h.
 There is no evidence clinically or experimentally that
cooling for longer or deeper is beneficial. Cooling less
was effective in adults after cardiac arrest; in newborns
we have not examined this question.
 There is observational data on a small group of patients
that cooling after postnatal collapse or slightly premature
birth (gestational age of 34 and 35 weeks) is feasible.
 Caution with TH is necessary when there is evidence of
infection or bleeding.
 Hypothermia affects normal physiology as well as path-
ophysiology. Predictors for outcome are different in
cooled infants, including for those with severe injury.
 M. Thoresen / Seminars in Fetal & Neonatal Medicine 20 (2015) 66e71 71

Conict of interest statement [22] Thoresen M, Hellstrom-Westas L, Liu X, de Vries LS. Effect of hypothermia on
amplitude-integrated electroencephalogram in infants with asphyxia. Pedi-
atrics 2010;126:e131e139.
None declared. [23] Groenendaal F, Casaer A, Dijkman KP, Gavilanes AW, de Haan TR, ter Horst HJ,
et al. Introduction of hypothermia for neonates with perinatal asphyxia in the
Funding sources Netherlands and Flanders. Neonatology 2013;104:15e21.
[24] Jary S, Whitelaw A, Walloe L, Thoresen M. Comparison of Bayley-2 and
Bayley-3 scores at 18 months in term infants following neonatal enceph-
The work was funded mainly by the UK charity SPARKS alopathy and therapeutic hypothermia. Dev Med Child Neurol 2013;55:
(05BTL01), The Wellcome Trust, The Norwegian Medical Research 1053e9.
[25] Smit E, Liu X, Jary S, Cowan F, Thoresen M. Cooling neonates who do not full
Council (214356), and The Lrdal Foundation for Acute Medicine. the standard cooling criteria e short- and long-term outcomes. Acta Paediatr
2014 Aug 27. http://dx.doi.org/10.1111/apa.12784 [Epub ahead of print].
Acknowledgement [26] Whitelaw A, Bridges S, Leaf A, Evans D. Emergency treatment of neonatal
hyperammonaemic coma with mild systemic hypothermia. Lancet 2001;358:
36e8.
Dr Elisa Smit is acknowledged for data on cooling outside [27] Roelfsema V, Bennet L, George S, Wu D, Guan J, Veerman M, et al. Window
standard entry criteria. Dr Tommy Wood is acknowledged for of opportunity of cerebral hypothermia for postischemic white matter
injury in the near-term fetal sheep. J Cereb Blood Flow Metab 2004;24:
valuable comments on the manuscript and language editing. 877e86.
[28] Sabir H, Scull-Brown E, Liu X, Thoresen M. Immediate hypothermia is not
References neuroprotective after severe hypoxiaeischemia and is deleterious when
delayed by 12 hours in neonatal rats. Stroke 2012;43:3364e70.
[29] Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain:
[1] Perlman M, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al.
starting therapeutic hypothermia within three hours after birth improves
Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopul-
motor outcome in asphyxiated newborns. Neonatology 2013;104:228e33.
monary Resuscitation and Emergency Cardiovascular Care Science with
[30] ClinicalTrials.gov. Late hypothermia for hypoxiceischemic encephalopathy.
Treatment Recommendations. Circulation 2010;122:S516e38.
Available at: https://clinicaltrials.gov/ct2/show/NCT00614744.
[2] UK Resuscitation Council. Newborn life support. London: UKRC; 2010.
[31] Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia
[3] British Association of Perinatal Medicine. Position statement on therapeutic
is not neuroprotective when started after postischemic seizures in fetal sheep.
cooling for neonatal encephalopathy. London: BAPM; 2010.
Pediatr Res 1999;46:274e80.
[4] Thoresen M, Penrice J, Lorek A, Cady EB, Wylezinska M, Kirkbride V, et al. Mild
[32] Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, et al. Effect
hypothermia after severe transient hypoxiaeischemia ameliorates delayed
of depth and duration of cooling on deaths in the NICU among neonates with
cerebral energy failure in the newborn piglet. Pediatr Res 1995;37:667e70.
hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA
[5] Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal
2014;312:2629e39.
rescue with prolonged selective head cooling after ischemia in fetal lambs. J
[33] Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with head
Clin Invest 1997;99:248e56.
cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C)
[6] Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants
after perinatal asphyxia. Pediatrics 2003;111:244e51.
after perinatal asphyxia: a safety study. Pediatrics 1998;102:885e92.
[34] Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA,
[7] Agnew DM, Koehler RC, Guerguerian AM, Shaffner DH, Traystman RJ,
et al. Whole-body hypothermia for neonatal encephalopathy: animal obser-
Martin LJ, et al. Hypothermia for 24 hours after asphyxic cardiac arrest in
vations as a basis for a randomized, controlled pilot study in term infants.
piglets provides striatal neuroprotection that is sustained 10 days after
Pediatrics 2002;110:377e85.
rewarming. Pediatr Res 2003;54:253e62.
[35] Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloeck WG, Billi J, et al.
[8] Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, et al.
Therapeutic hypothermia after cardiac arrest: an advisory statement by the
Moderate hypothermia in neonatal encephalopathy: efcacy outcomes.
advanced life support task force of the International Liaison Committee on
Pediatr Neurol 2005;32:11e7.
Resuscitation. Circulation 2003;108:118e21.
[9] Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et
[36] Nielsen N, Wetterslev J, Cronberg T, Erlinge D, et al. Targeted temperature
al. Selective head cooling with mild systemic hypothermia after neonatal
management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J
encephalopathy: multicentre randomised trial. Lancet 2005;365:663e70.
Med 2013;369:2197e206.
[10] Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF,
[37] Karlsson M, Tooley JR, Satas S, Hobbs CE, Chakkarapani E, Stone J, et al.
et al. Whole-body hypothermia for neonates with hypoxiceischemic en-
Delayed hypothermia as selective head cooling or whole body cooling does
cephalopathy. N Engl J Med 2005;353:1574e84.
not protect brain or body in newborn pig subjected to hypoxiaeischemia.
[11] Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al.
Pediatr Res 2008;64:74e8.
Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J
[38] Hoque N, Liu X, Chakkarapani E, Thoresen M. Minimal systemic hypothermia
Med 2009;361:1349e58.
combined with selective head cooling evaluated in a pig model of hypo-
[12] Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic
xiaeischaemia. Pediatr Res 2015 [in press].
hypothermia and rewarming in infants with hypoxiceischemic encephalop-
[39] Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for
athy. Pediatrics 2000;106:92e9.
newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst
[13] Azzopardi D, Robertson NJ, Cowan FM, Rutherford MA, Rampling M,
Rev 2013;(1):CD003311.
Edwards AD. Pilot study of treatment with whole body hypothermia for
[40] Wood T, Osredkar D, Sabir H, Falck M, Maes E, Thoresen M. Cooler isn't better
neonatal encephalopathy. Pediatrics 2000;106:684e94.
e hypothermia at three different temperatures does not provide neuro-
[14] Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx 2006;3:
protection in a rat model of severe neonatal hypoxiceischaemic encepha-
154e69.
lopathy. Vancouver: Paediatriac Academic Societies; 2014. p. 4650e8. http://
[15] Guillet R, Edwards AD, Thoresen M, Ferriero DM, Gluckman PD, Whitelaw A,
www.abstracts2view.com/pas/view.php?nuPAS14L1_4650.8.
et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for
[41] ClinicalTrials.gov. Therapeutic controlled hypothermia in the treatment of
neonatal encephalopathy. Pediatr Res 2012;71:205e9.
neonates with severe necrotizing enterocolitis (CoolNEC). Available at:
[16] Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al.
https://clinicaltrials.gov/ct2/show/NCT01330576.
Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J
[42] Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard R, Edwards AD, et al.
Med 2012;366:2085e92.
Determinants of outcomes after head cooling for neonatal encephalopathy.
[17] Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, et al.
Pediatrics 2007;119:912e21.
Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J
[43] Chakkarapani E, Davis J, Thoresen M. Therapeutic hypothermia delays the C-
Med 2014;371:140e9.
reactive protein response and suppresses white blood cell and platelet count
[18] Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al.
in infants with neonatal encephalopathy. Archs Dis Childh Fetal Neonatal Ed
Neurological outcomes at 18 months of age after moderate hypothermia for
2014;99:F458e63.
perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of
[44] Mourvillier B, Tubach F, van de Beek D, Garot D, Pichon N, Georges H, et al.
trial data. BMJ 2010;340:c363.
Induced hypothermia in severe bacterial meningitis: a randomized clinical
[19] Odd DE, Lewis G, Whitelaw A, Gunnell D. Resuscitation at birth and cognition
trial. JAMA 2013;310:2174e83.
at 8 years of age: a cohort study. Lancet 2009;373:1615e22.
[45] Fischer D, Allendorf A, Buxmann H, Weiss K, Schloesser RL. Purpura fulminans
[20] van Handel M, Swaab H, de Vries LS, Jongmans MJ. Behavioral outcome in
after therapeutic hypothermia in an asphyxiated neonate with strepto-
children with a history of neonatal encephalopathy following perinatal
coccemia. Am J Perinatol 2014;31:257e60.
asphyxia. J Pediatr Psychol 2010;35:286e95.
[46] Osredkar D, Thoresen M, Maes E, Flateb T, Elstad M, Sabir H. Hypothermia is
[21] Orbach SA, Bonifacio SL, Kuzniewicz MW, Glass HC. Lower incidence of seizure
not neuroprotective after infection-sensitized neonatal hypoxiceischemic
among neonates treated with therapeutic hypothermia. J Child Neurol
brain injury. Resuscitation 2014;85:567e72.
2014;29:1502e7.