(2024) 24:509
Tran et al. BMC Pediatrics
https://doi.org/10.1186/s12887-024-04987-6

BMC Pediatrics

RESEARCH

Open Access

Cooling during transportation of newborns
with hypoxic ischemic encephalopathy using
phase change material mattresses in lowresource settings: a randomized controlled trial
in Hanoi, Vietnam
Hang. T. T. Tran1,2*, Dien. M. Tran2, Ha. T. Le2, Lena Hellström‑Westas3, Tobias Alfvén1,4† and Linus Olson5†

Abstract
Objective To determine the effectiveness of phase-change-material mattress (PCM) during transportation of new‑borns with hypoxic ischemic encephalopathy (HIE).
Study design Randomized controlled trial of newborns with HIE from June 2016 to December 2019. Patients wererandomized to transport with PCM or without PCM (control) when transferred to a cooling center in northern Viet‑nam. Primary outcome measure was mortality rate, secondary outcomes including temperature control and adverse
effects.
Result Fifty-Two patients in PCM-group and 61 in control group. Median rectal temperature upon arrival was 34.5 °C(IQR 33.5–34.8) in PCM-group and 35.1 °C (IQR 34.5–35.9) in control group (p = 0.023). Median time from birth to reachtarget temperature was 5.0 ± 1.4 h and 5.5 ± 1.2 h in the respective groups (p = 0.065). 81% of those transportedwith PCM versus 62% of infants transported without (p = 0.049) had reached target temperature within the 6-htimeframe. There was no record of overcooling (< 32 °C) in any of the groups. The was no difference in mortality rate
between the two groups (33% and 34% respectively (p > 0.05)).
Conclusion Phase-change-material can be used as a safe and effective cooling method during transportationof newborns with HIE in low-resource settings.
Trial registration The study was retro-prospectively registered in Clinical Trials (04/05/2022, NCT05361473).
Keywords Asphyxia, Cooling, Encephalopathy, Low-income setting, Phase change materials†

Tobias Alfvén and Linus Olson shared last authorship.

*Correspondence:
Hang. T. T. Tran
hang231@gmail.com
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Tran et al. BMC Pediatrics(2024) 24:509

Background
Neonatal hypoxic-ischemic encephalopathy (HIE),
caused by a lack of blood flow and oxygen to the brain
at birth, occurs in 10–20/1000 live births in low-middle-income countries (LMICs) [1]. In Vietnam, birthasphyxia accounts for 14% of all neonatal mortality [2],with regional variation and reported rates as high as 33%
in certain regions [3, 4]. Although the incidence of birthasphyxia in Vietnam is high, there is still limited experience with therapeutic hypothermia (TH) treatment, as inother LMICs.
Meta-analysis of studies from high-income countries(HICs) show that induced hypothermia is associated with
reduced risk of death or major neurodevelopmental disability by 18 months of age [5, 6]. The benefits of cooling, however, is insufficiently studied and requires further
evaluation in LMICs [7, 8].
Evidence from animal and newborn studies has indicated that the window of opportunity to start cooling iswithin 6 h after birth [9, 10]; hence, transportation time
could delay hypothermia treatment, consequently altering the safety or effectiveness of TH treatment and neurological outcomes [11].
In order to optimize the neuroprotective effect in newborns with HIE, cooling should start as early as possible,
both actively and passively. Several studies have shownthat passive cooling (e.g., removal of clothes, turning off
heating devices to allow the baby to cool down naturally)is less effective and has a higher risk of overcooling compared to active cooling using servo-controlled equipment[12–14]. Despite the demonstrated benefits of servocontrolled devices when used in transport [13, 15] more
recent studies continue to show achieving target temperature within the 6-h window remains a challenge for THs
even in HIC settings with proportions between 55 and63% [16] let alone in LMICs like Vietnam.
Phase change material (PCM) has been well studied inboth animals and newborn infants for its effectivenessand safety in therapeutic hypothermia treatment [17, 18].
A PCM-based device has been shown to be comparable
to standard servo-controlled equipment in maintaining the target temperature [19, 20]. A pilot study implementing PCM to cool asphyxiated newborns in Vietnam
has proven that it is an effective yet easy to use methodof cooling in a low-resource neonatal intensive care unit
[21].
Following our previous study, the aim of this study was
to determine the feasibility and effectiveness of phasechange-material mattresses during transportation of
asphyxiated newborns with suspected HIE, with the aimof reducing the time to initiate therapeutic cooling in
low-resource settings.

Page 2 of 8

Participants and methods
Participants

Following a pilot study showing that PCM is feasible andsafe for inducing TH [21], we conducted a randomized
controlled trial study of patients from seven hospitals
with up to 200 km transport distance to a tertiary center.
The inclusion criteria were infants ≥ 36 weeks gestational
age and ≤ 6 h after birth with either Apgar score ≤ 5 at
10 min or continued need for resuscitation at 10 min or
pH < 7.0 and/or base deficit > 16 mmol/L and sign of moderate to severe encephalopathy (altered consciousness,abnormal tone). Infants were excluded if they were > than
6 h old at the time of referral/evaluation, had coagulopathy with active bleeding, were prenatally diagnosed withsyndromes, or had malformations or metabolic disorders
not compatible with survival [22]. Prior to the study, visits to assess the hospital and training sessions had beenorganized to enhance neonatal unit doctors and nurses’
knowledge at all sites concerning the background of thestudy, the use of a PCM mattress, data recording, andassessment of patients. Parents/guardians of asphyxiatednewborns were approached regarding participation in
the study once the patient met criteria for cooling. This
study was intended to be a feasibility study to assess thesafety and applicability of using PCM for transportationof asphyxiated newborns compared to passive cooling(standard care). According to our pilot study, the mortality rate of HIE infants was 35% [21], sample size was calculated showing that 67 infants in each group would be
sufficient to give a 95% confidence level with a power of
80% to detect a difference of 15% mortality rate between
the two groups. We therefore planned to recruit 20
patients in each of the seven study sites, giving a total of
70 infants per group.
Study design and intervention

After delivered at provincial hospital, the babies werestabilized by local team and if cooling criteria were met,
local team will contact the tertiary hospital in request fortransfer.
Each hospital was provided with sealed envelopes containing information for PCM or control by the study
team. Randomization was stratified by each of the 7referring hospitals to one of the two groups. One groupcooled by PCM mattress (Medical Cooling Sweden AB;
by TST AB, Kinna, Sweden) during transportation. The
PCM mattress that was used contained 8 PCM packs
with a specific melting point of 32°C, built into two layers of 4 × 2 PCM sheets. The mattress was covered witha fabric with possibilities for providing temperaturechanges between the PCM and the patient through thermal conductance. The newborn is positioned on theTran et al. BMC Pediatrics(2024) 24:509

PCM mattress, ensuring optimal contact with the coolingsurface and secure fixation during transport (Illustrated
Fig. 1).
In the control group, patients were passively cooled byturning off all external heating sources. The babies weretransported in road ambulances, placed on an ambulance
stretcher with only one layer of clothes on, no extra coverby blanket (referring hospitals do not have transportincubators) during transportation, which enabled thebabies to chill spontaneously at air temperature.
Axillary temperature and environment temperature
were measured before transport and every 30 min during
the transportation for both groups. The infant’s condition
was clinically monitored by the accompanying hospital
staff, but there was no continuous monitoring of heart
rate or oxygen saturation during transport. On arrivalat VNCH, the infants were evaluated for continuation ofcooling or initiation of cooling, respectively. All received
hypothermia treatment with PCM mattress.
Both groups received cooling therapy with a target temperature of 33.5–34.5 °C for 72 h and standard medicalcare. On admission, the severity of the infant’s encephalopathy was assessed by modified Sarnat staging while
Thompson score was used daily to assess the clinical progress of the newborn. It involves evaluating various clinical signs such as level of consciousness, tone, reflexes,
seizures, and respiratory function, with each sign scoredto provide an overall severity rating [23]. Short-term
adverse effects of cooling, such as respiratory cardiovascular complications (bradycardia, hypotension, pulmonary hypertension), electrolyte imbalance (hypokalemia,
hyponatremia), and coagulopathy – platelet dysfunction,
were recorded during treatment.
Outcome measures

In this study, the primary aim was to evaluate the effectiveness of the phase-change-maternal (PCM) mattressFig. 1 Illustration of an infant on PCM mattress

Page 3 of 8

in the transportation of newborns with hypoxic-ischemic
encephalopathy (HIE). The primary outcome measure
was mortality, serving as a critical indicator of the PCM
mattress’s overall impact on patient survival. Secondary
outcomes included rectal temperature on arrival, time toreach target temperature 33.5 °C (postnatal age), neurology assessment on arrival and at discharge (for survivors),
Short term adverse effects of cooling included: bradycardia (heart rate < 100 beats per minute, hypotension (meanarterial blood pressure < 10th percentile for gestationalage), persistent pulmonary hypertension (diagnosed clinically and with echocardiography), hypokalemia (serum
potassium level < 3.5 mEq/L), hyponatremia (serum
sodium level < 135 mEq/L) and coagulopathy (bleeding
and depletion of anti-coagulant factors). By examining
mortality, temperature control, and other relevant outcomes, we aimed to provide a holistic evaluation of the
PCM mattress’s effectiveness in improving the care ofnewborns with HIE during transport.
Statistical analyses

Demographic factors and clinical characteristics weresummarized with counts (percentages) for categoricalvariables, mean (standard deviation [SD]) for normally
distributed continuous variables or median (interquartile or entire range) for other continuous variables. For
each group, differences were assessed using Student’s ttest (normal distribution) or the Mann Whitney U test
(skewed distribution). Data were analyzed by using SPSS.
P value < 0.05 was considered statistically significant.

Results
During the three-year study period (from September 1st2016 to December 31st 2019), there were in total 118
infants transferred from the seven study hospitals: 55 in
the PCM group, and 63 in the control group. The average time for transfer in PCM group and control was 2.1 h(0.5–2.8) and 2.2 h (0.5–3) respectively. Upon arrival at
VNCH, during re-evaluation, the encephalopathy was
mild in five patients (3 in PCM group, 2 in non-PCM
group), and cooling was therefore stopped for thesechildren, and they were excluded from the analysis. The
study participants are summarized in Fig. 2.
Baseline maternal and neonatal characteristics for bothgroups are presented in Table 1.
Newborns had a mean gestation of 39 (± 1.1) weeks
in both groups, and the majority were male, with 37(71%) in the PCM group and 39 (64%) in the control
group. There was no significant difference between thetwo groups in terms of maternal age or mode of delivery. Close to 50% of cases required emergency c-section
due to intrapartum complications such as fetal distress, cord prolapse, bleeding, or other complications.

Tran et al. BMC Pediatrics(2024) 24:509

Page 4 of 8

Fig. 2 Enrolment, Randomization of the study participants

Table 1 Maternal and neonatal baseline characteristics. Figures are numbers (percentages) and means (standard deviation)
Characteristic

PCM group(n = 52)

Control group(n = 61)

P value

Maternal
Age – years

27 ± 526 ± 60.160

Intrapartum complications – no. (%)

43

44

0.083

Fetal heart-rate deceleration

15 (29)18 (34)

Cord prolapses

2 (4)

0 (0)

Shoulder dystocia

3 (6)

2 (4)

Maternal hemorrhage

2 (4)

3 (6)

Vaginal delivery/Instrumental Delivery

28 (54)34 (56)Emergency caesarean delivery

24 (46)27 (44)Mode of delivery – no. (%)

0.671

Neonatal
Male – no. (%)

37 (71%)39 (64%)

0.522

Gestational (weeks)

39 (± 1.1)

39 (± 1.2)

0.634

Birthweight (grams)

3210 (± 1040)

3165 (± 416)

0.754

Apgar score ≤ 5 – no. (%) at 10 m
­ ina

22 (100%)

28 (100%)

Age at admission (hours from birth)

3.6 ± 1.4

3.9 ± 1.4

0.119

Transport distance, hours by road ambulance (Median, range)

2.1 (0.5 – 2.8)

2.2 (0.5 – 3)

0.204

Time to reach target temp 33.5 °C to 34.5 °C – (hours from birth)

5.0 ± 1.4

5.5 ± 1.2

0.065

Number of patients reaching target temp within 6 h of birth – no. (%)

42 (80.8%)

38 (62.3%)

0.049
0.125

Rectal temp at randomization, before transport (°C)

35.8 ± 0.6

36 ± 0.8

Seizure on admission – no. (%)

5 (10)3 (5)Moderate—Sarnat stage II (n)18 (35)23 (38)Severe—Sarnat stage III (n)34 (65)38 (62)

Level of encephalopathy – no. (%)

a

0.625

Apgar score at 5 min and 10 min were available for only 22 newborns in PCM group and 28 newborns in control groupTran et al. BMC Pediatrics(2024) 24:509

Eligibility criteria for transportation and evaluation
for cooling were adapted to previous multicenter studies [22] and based on either Apgar scores or need forcontinuation of resuscitation at 10 min, because bloodgases were not routinely reported or assessed.
In the PCM group, 15 (29%) newborns had clinicalseizures on admission, with a mean age at admission of
3.6 h ± 1.4. In the non-PCM group, 23 (38%) newborns
had clinical seizures on admission, with a mean age at
admission of 3.9 h ± 1.4. Anticonvulsant use was similar
in both groups.
Figure 3 shows the mean temperature of the newborns in both groups at two different time points: on
departure from the referring hospital and on arrival at
VNCH. Upon arrival to VNCH, the mean rectal temperature in the PCM group was significantly lower thanin the control one: 34.5 °C (IQR 33.5 – 34.8) compared
to 35.1 °C (IQR 34.5 – 35.9) (p = 0.023). There was norecord of excessive hypothermia (< 32 °C) on admission for any of the groups. Consequently, the mediantime to reach target cooling temperature from birth in
the PCM group was 5 ± 1.4 h, while it took 5.5 ± 1.2 h
for the control group to reach the target cooling temperature (p = 0.065). 42/52 patients (81%) of thosetransported with PCM versus 38/61 (62%) of infants

Page 5 of 8transported without (p = 0.049) had reached target
temperature within the 6-h timeframe.
There was no significant difference in Thompson scores
between the two groups on arrival and on consequentdays.
In total, 38 newborns died before discharge from hospital: 17 in the PCM group and 21 in the control group.
In the PCM group, the newborns died from the following causes: encephalopathy-related complications (n = 13[74%]), persistent pulmonary hypertension (n = 3 [18%]),and sepsis (n = 1 [6%]). In the control group, the primarycause of death was also encephalopathy-related complications (n = 18 [86%]); other causes including persistentpulmonary hypertension (n = 2 [4%]) and pneumothorax(n = 1 [2%]). The proportion of deaths according to Sarnat
stage was similar across groups (Table 2). Among the 75
survivors, 69 (92%) completed follow-up until 18 months.
Nineteen children developed cerebral palsy (8 diplegia, 3hemiplegia, 8 dyskinetic), and 11 had delayed neurodevelopment [24].

Discussion
In this randomized controlled study, we show that phasechanging material (PCM) can be used as a safe and effective cooling method during transportation of newborns
with HIE. The mortality rate was similar between the two

Fig. 3 Box plot for temperature measurement at referring hospital and on arrival at VNCH. The area between the redlines shows the target
temperature range of 33.5 °C to 34.5 °C

Tran et al. BMC Pediatrics(2024) 24:509

Page 6 of 8

Table 2 Clinical outcomes
Variables

PCM group (n = 52) Control
group(n = 61)

P value

Encephalopathy score (Thompson score)Day 1, Mean, min–max
At discharge, Mean,min–max

16 (9 – 21)

17 (9 – 22)

n.s

5 (0 – 18)

6 (0 – 18)n.sComplications during cooling – no. (%)
Hypotension ± inotropes 30 (58)33 (54)n.s

Pneumothorax

0

n.s

2 (4)

Uncontrollable seizures

4 (8)

3 (5)

n.s

Sepsis10 (19)10 (16)n.s

MRI at day 7–10 – no. (%)
White matter injury

10 (19)11 (18)n.s

Cerebral hemorrhage

3 (6)

1 (2)

n.s

Brain edema

2 (4)

1 (2)

n.s

Brain atrophy

0

1 (2)

n.s

Deaths – n (%)
Total

17 (33%)21 (34%)n.s

Sarnat stage II

2

3

n.s

Sarnat stage III

15

18

n.s

groups; however, the study was underpowered to detect a
difference between two groups. Target temperature wasreached faster in the group where PCM was used duringtransportation, and there were no complications duringtransportation.
In the present study, the overall mortality rate was 34%,
which was significantly higher in comparison to 19% in
previous trials from high-income countries [25]. However, the mortality rate was similar to other LMIC settings, such as Nepal (31%) [26], and even slightly lower
than, e.g., India, Sri Lanka, and Bangladesh (42%) [8]. The
proportion of deaths according to Sarnat stage was similar across groups, and up to 50% of infants with Sarnat
stage III encephalopathy died. Indeed, studies from Nepal
have shown that, in settings where long-term ventilationand stabilization are not available, the mortality rate fornewborns with Sarnat stage III neonatal encephalopathy
can be as high as 100% [26]. Comparable to many cooling studies, there were no differences between the twogroups in the present study in terms of adverse events,
such as hypotension, arrhythmias, coagulation dysfunction, skin injury due to cooling, or infection [27].
The results from our study, with combined infantmortality and severe neurological disability of 55% in
infants treated with TH [24], were comparable to both
the results in the randomized HELIX trial, in part performed during the same time. Possible explanations
for the worse outcomes in LMICs include the larger

proportion of newborns requiring transport and referral from other hospitals, longer duration of the hypoxic
insult, and a higher proportion of newborns having clinical seizures, all of which are comparable to the findingsof this study. Since there are multiple factors that could
influence the results of hypothermic neuroprotection,
the question of whether we should stop cooling newborns with HIE in LMICs should be investigated further.
There are many differences in the epidemiology and outcome of newborns with encephalopathy in low-resource
settings such as higher incidence of hospital-acquired
infections like sepsis or pneumonia in Vietnam’s hospitals [28]. Additionally, there is convincing evidence thatsuggests that a combination of infection and ischemia
results in more severe brain injuries and increases in therisk of adverse outcomes [29, 30], which is possibly one of
the factors responsible for the poorer neurological outcome reported from low and mid-resource settings [26].
Among the 113 patients in this study, we suspected earlyonset sepsis by history in 10 patients, only 2 patients(0.2%) were diagnosed with sepsis by positive blood cultures. In our study, none of the children had documented
metabolic disorders.
The transfer of patients took 2.1 h (0.5 – 2.8) in PCM
group and 2.2 h (0.5 – 3) in control, with a median temperature on arrival 0.6 °C lower in the PCM group (34.5°C) than in the control group (35.1 °C). In a subtropical region like Vietnam, average temperatures range
from high of 35.6 °C (96.1°F) to low of 14.6 °C (58.3°F),
with an average yearly temperature of 24.8 °C (76.7°F)”.
Under such thermal conditions, passive cooling may beless effective than more efficient methods of cooling.
When comparing the temperature on arrival with otherstudies from similar settings, it was lower than in boththe NICHD trial (36.6 ± 1.0 °C) [25], where all patientswere inborn, and in the Thayil S et al. trial (35.2 ± 1.3 °C)[20]. The target temperature of 33.5 °C was achieved at
a median of 1.5 h earlier for the PCM group than thecontrol group, which is a possible advantage, since studies have shown that reaching the target temperature
early is often associated with better motor outcomes at
18 months in surviving newborns [10]. In a large cohortof 207 infants in Canada who received cooling for HIE,
it was shown that initiating cooling before and duringtransfer is critical for achieving the target temperaturesooner, which is a key factor for improving outcomes [31,32]. Lemyre et al. also suggested that the severity of theencephalopathy was associated with the time to reach thetarget core temperature. We did not demonstrate a statistically significant difference in time to reach target temperature between groups (p = 0.062). However, we diddemonstrate a significant difference in the proportion of
infants reaching target temperature by 6 h of age between

Tran et al. BMC Pediatrics(2024) 24:509

groups (80.8% in infants transported with PCM versus
62.3% of infants transported without, p = 0.049). This difference means that a larger proportion of infants received
neuroprotection within the narrow six-hour timeframe
shown to be efficacious in animal and human studies
of TH for HIE. Transport over both short and long distances makes achieving and maintaining target temperature a great challenge globally. Studies in both LMICs and
HICs show that delays in the initiation of cooling therapy(even though still within the six-hour window of the protocol) result in longer time to attain target temperaturesand likely contribute to worse outcomes. [33, 34].
In our study, no patient in either of the two groups
developed severe hypothermia (< 32 °C). However, several authors have raised concerns that initiation of cooling during transport may increase the risk of excessive
cooling [35, 36] especially when ambulances in most
LMIC settings are used solely for transport and not as
an emergency care vehicle, due to poorly equipped facilities and lack of trained medical staff [37, 38]. In comparison, removal of an external heat supply in 18 transported
newborns in Sweden resulted in 3 (17%) newborns
becoming overcooled to below 32 °C [36]. Similarly,
Zanelli et al. reported that in their study of 11 newborns,
two newborns were significantly overcooled (29.2 °C and29.6 °C) upon arrival at the hospital by passive cooling. In
another study of 35 newborns, where active cooling was
conducted by placing cool packs in an incubator, 34% of
newborns had core temperatures below 32 °C on arrivalat the cooling center [39].

Conclusion
Initiating therapeutic hypothermia with a PCM mattressduring ambulance transportation is feasible and safe,
allowing for significantly earlier initiation and attainmentof target temperatures. While this approach shows promise, further research is needed to definitively determine
its potential benefits for neonates with hypoxic-ischemic
encephalopathy, as current evidence primarily comesfrom animal studies.
Trial registration
The study was retro-prospectively registered in Clinical
Trials (04/05/2022, NCT05361473).
This study was conducted in strict accordance with theConsolidated Standards of Reporting Trials (CONSORT)
guidelines. All aspects of the study, including participant
enrollment, allocation, intervention, follow-up, and data
analysis, were designed, and reported to ensure transparency, rigor, and reproducibility in line with the CONSORT recommendations. Detailed checklists have been
provided as supplementary materials to illustrate thestudy’s adherence to these standards.

Page 7 of 8

Abbreviations
HICs	High-income countries
HIE	Hypoxic ischemic encephalopathy
LMICs	Low-middle income countries
NICU	Neonatal intensive care unit
PCM	Phase change materials
TH	Therapeutic hypothermia
VNCH	Vietnam National Children’s Hospital
Acknowledgements
We would like to acknowledge all participants in our studies, all referring hos‑pitals: Hanoi OBGY Hospital, Ha Dong General Hospital, Hung Yen Provincial
hospital of Obstetrics and Pediatrics, Thai Binh Provincial Hospital Pediatrics,
Hai Duong Provincial hospital of Pediatrics, Bac Giang Provincial hospital of
Obstetrics and Pediatrics, Vinh Phuc Provincial hospital of Obstetrics and Pedi‑
atrics and Dr Linus Olson from TRAC who have student exchange and capacity
building between Sweden and Vietnam possible. The Swedish researchcouncil, VR for support.
Authors’ contributions
All authors have accepted responsibility for the entire content of this manu‑
script and approved its submission. Dr H.T.T.T had primary responsibility for
protocol development, patient screening, enrollment, outcome assessment,
preliminary and final data analysis and writing the manuscript; Dr T.A andDr L.O supervised the design and execution of the study and contributed to
the writing of the manuscript; Drs H.T.L participated in the patient screening,
enrollment and data collection; Drs D.M.T, L.H.W supervised the execution of
the study and contributed to the writing of the manuscript.
Funding
Open access funding provided by Karolinska Institute.
Availability of data and materials
The data and material used in this study are available from the corresponding
author on reasonable request.

Declarations
Ethics approval and consent to participate
This study was approved by the Ethical Review Board of National Hospitalof Pediatrics (renamed as Vietnam National Children’s Hospital since 2017)
Research Institute for Child Health (RICH) (NHP—RICH- 13–002).
Written informed consent was obtained from all participants’ parent/legal
guardian to participate in the study prior to allocated to treatment.
Consent for publication
Written informed consent for publication of identifying images or otherpersonal or clinical details was obtained from all participants’ parent/legal
guardian.
Competing interests
The authors declare no competing interests.
Author details
1
Department of Global Public Health, Karolinska Institutet, Stockholm,
Sweden. 2 Vietnam National Children’s Hospital, Hanoi, Vietnam. 3 Department
of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
4
Sachs’ Children and Youth Hospital, Stockholm, Sweden. 5 Department
of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
Received: 9 April 2024 Accepted: 31 July 2024

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