Indian Pediatr 2018;55: 201-205
Phase Changing Material for Therapeutic
Hypothermia in Neonates with Hypoxic Ischemic Encephalopathy – A
and Somashekhar Nimbalkar11
From Departments of Neonatology; 1CMC, Vellore, Tamil
Nadu; 2JIPMER, Puducherry; 3Jubilee Mission
Medical College and Research Institute, Thrissur, Kerala; 4St.
John’s Medical College Hospital, Bengaluru; 5The Cradle (by
Apollo), Gurgaon; 6KMC, Manipal; 7Sri Ramachandra
Medical College Chennai; 8Fernandez Hospital, Hyderabad;
9Neoclinic, Jaipur; 10Narayana Multispeciality
hospital, Ahmedabad, Gujarat; and 11Department of Pediatrics,
Pramukhswami Medical College, Karamsad, Gujarat; India.
Correspondence to: Dr. Niranjan Thomas, Department of Neonatology,
Christian Medical College, Vellore 632 004, Tamil Nadu, India.
Received: February 17, 2017;
Initial review: June 19, 2017;
Accepted: November 27, 2017.
Published online: December 14, 2017.
Objective: To assess the
feasibility and safety of cooling asphyxiated neonates using phase
changing material based device across different neonatal intensive care
units in India.
uncontrolled clinical trial.
Setting: 11 level 3 neonatal
units in India from November 2014 to December 2015.
Participants: 103 newborn infants
with perinatal asphyxia, satisfying pre-defined criteria for therapeutic
hypothermia was provided using phase changing material based device to a
target temperature of 33.5±0.5oC, with a standard protocol. Core body
temperature was monitored continuously using a rectal probe during the
cooling and rewarming phase and for 12 hours after the rewarming was
Outcome measures: Feasibility
measure - Time taken to reach target temperature, fluctuation
of the core body temperature during the cooling phase and proportion of
temperature recordings outside the target range. Safety
measure - adverse events during cooling
Results: The median (IQR) of time
taken to reach target temperature was 90 (45, 120) minutes. The mean
(SD) deviation of temperature during cooling phase was 33.5 (0.39) ºC.
Temperature readings were outside the target range in 10.8% (5.1% of the
readings were <33oC and 5.7% were >34oC). Mean (SD) of rate of rewarming
was 0.28 (0.13)oC per hour. The common adverse events were shock/
hypotension (18%), coagulopathy (21.4%), sepsis/probable sepsis (20.4%)
and thrombocytopenia (10.7%). Cooling was discontinued before 72 hours
in 18 (17.5%) babies due to reasons such as hemodynamic
instability/refractory shock, persistent pulmonary hypertension or
bleeding. 7 (6.8%) babies died during hospitalization.
Conclusion: Using phase changing
material based cooling device and a standard protocol, it was feasible
and safe to provide therapeutic hypothermia to asphyxiated neonates
across different neonatal units in India. Maintenance of target
temperature was comparable to standard servo-controlled equipment.
Keywords: Cooling devices, Perinatal
Therapeutic hypothermia (TH) reduces mortality and
neurodevelopmental morbidity in asphyxiated neonates and is now the
standard of care for asphyxiated neonates in high-income countries .
As servo-controlled equipment are expensive, many innovative low-cost
methods have been developed for cooling and are being used in low- and
middle-income countries (LMICs). A recent systematic review of TH in
LMICs concluded that TH was not associated with a statistically
significant reduction in neonatal mortality or neurodevelopmental
morbidity . One among the reasons stated was the probable
inefficiency of the low technology cooling devices. The review
emphasized the need for further studies on safety and efficacy of TH in
LMICs using low-cost device before it could be offered in routine
clinical practice .
Phase changing material (PCM) is one such low-cost
technology used for cooling asphyxiated neonates [3,4]. MiraCradle
- Neonate Cooler is a PCM-based cooling device
that has recently been developed and used in India. Though we have
previously reported successful use of PCM-based device to provide TH,
the question remains whether the same results can be replicated in other
centers . Hence we prospectively collected data from eleven centers
to analyze the feasibility and safety of providing TH using the
This was a multi-centric, uncontrolled clinical
trial, done in 11 centers in India from November 2014 to December 2015.
We used Miracradle - Neonate Cooler (Pluss Advanced Technologies) to
provide TH. The manufacturer of the device and Christian Medical College
(CMC) Vellore, the development partner, conducted a workshop at CMC,
Vellore in August 2014. In this workshop, neonatologists from all the 11
centers were trained on providing TH using PCM-based device, and various
clinical aspects of TH were discussed. The study centers were level-3
neonatal intensive care units (NICUs) from both public and private
sector who were already using cool gel packs for TH in neonates and/or
expressed interest in using the PCM-based device for the purpose. None
of the centers were using servo-controlled equipment for TH. Thereafter,
the cooling device was supplied to all the centers along with relevant
We developed a registry to record the temperature,
complications and other relevant data of the cooled infants. The
document was supplied in hard as well as soft copy to all the centers
and the data was collected prospectively over the study period. All the
centers got approval from their institutional ethical board to use the
equipment and collect the data for publication.
We included infants
³35 weeks gestational
age and ³1800
grams with a minimum of one physiological (Inborn babies – cord blood pH
<7 or base deficit >12; 5-minute APGAR <5; need for resuscitation for
>10 minutes. Outborn babies – a history of not having cried/breathed
immediately after birth; given assistance for breathing soon after
birth; 5-minute APGAR <5) and one neurological criteria (moderate or
severe encephalo-pathy as per modified Sarnat staging ; seizures).
Babies were excluded from the study if they had
chromosomal disorder or major congenital anomaly or inability to start
cooling before 6 hours of age.
The target temperature was 33.5±0.5ºC.
TH was started within 6 hours after birth and continued for 72 hours,
followed by slow rewarming over 10-12 hours at the rate of 0.2-0.5ºC
per hour. Core body temperature was monitored continuously using a
rectal probe during the cooling and rewarming phase and for 12 hours
after the rewarming was complete. The rectal probe was inserted to a
depth of 2-3 cm and it was sterilized with ethylene oxide gas after use.
MiraCradle-Neonate Cooler has a cradle made of
non-conducting material, PCM blocks kept in the hollowed-out area and a
conducting mattress above the PCM blocks, on which the baby is nursed.
The PCM blocks are stored in the refrigerator (2-8ºC)
and should be solid when taken for use. They were disinfected with
surgical spirit. Two types of PCM blocks were used, FS-29 (FS, form
stable) with melting point of 29ºC
and FS-21 with melting point of 21ºC.
During the induction phase, both FS-29 and FS-21 were
used to decrease the baby’s core temperature to the target range as
quickly as possible. When the temperature reached 33.8ºC,
the FS-21 was removed and only FS-29 was used during the maintenance
phase. The upper and lower alarm limits were set on the multi-parameter
monitor at 33.8ºC and 33.2ºC,
respectively. If the baby’s temperature reached
FS-21 was added till the temperature came down to 33.5ºC.
If the temperature reached
(lower alarm limit), steps taken to increase the core temperature were
placing a sheet between the PCM bed and the baby, covering the baby with
another sheet or switching on the radiant warmer. The radiant warmer was
used in manual mode with an output of 10% to start with, and adjusted in
increments or decrements of 5% depending on the baby’s temperature.
Continuous monitoring of vital parameters was done.
The study infants had a central venous line and an arterial line
whenever feasible. Blood counts, prothrombin time (PT) and activated
partial thromboplastin time (aPTT), serum creatinine, serum
electrolytes, liver enzymes and C-reactive protein (CRP) were monitored
Sedation was not routinely given during cooling.
Sedation/analgesia was given according to the protocol of the unit. All
the other treatment modalities including ventilation, medications
(antibiotics, anticonvulsants and inotropes) and use of blood products
were done as per the protocol of individual units.
The study enrolled 103 neonates [JIPMER, Puducherry
(25), CMC Vellore (23), JMMC, Thrissur (15), SJMC, Bangalore (n=10),
The Cradle, Gurgaon (10), KMC, Manipal (9), SRMC, Chennai (3), Fernandez
Hospital Hyderabad (3), Cloudnine Hospital Gurgaon (2), Neo Clinic
Jaipur (2) and Shaiva Critical Care Ahmedabad (1)]. The mean (SD)
gestational age and birth weight was 38.5 (1.5) and 2925 (458),
respectively. Three (2.9%) infants had mild, 81 (78.6%) had moderate and
19 (18.4%) infants had severe encephalopathy; 58 (56.3%) babies had
TABLE I Temperature and Cooling Profile of Enrolled Neonates (N=103)
Age of initiation of cooling (h)
Rectal temperature at initiation of cooling (oC)
*Time taken to reach target temperature (min)
90 (45, 120)
Temperature during cooling phase, (oC)
Temperature readings outside the target range
% below 33oC
% above 34oC
Rewarming rate (oC/ h),
Values in mean (SD) or *Median (IQR).
The temperature and cooling profile is provided in
Table I and Web Fig. 1. Cooling had to be
discontinued in 18 (17.5%) infants. The reasons included hypotension
(8), PPHN (4), withdrawal by parents (5) and bleeding (1). In the subset
of babies in whom cooling was withdrawn, the mean (SD) temperature
during the cooling phase was 33.5 (0.48)ºC
and 15.0% of the readings were outside the target range (10.6% readings
were <33ºC and 4.9% were >34ºC).
Table II shows the adverse events in the
cooled neonates. The most frequent events were related to hypotension,
coagulopathy and sepsis. Seven (6.8%) babies died before discharge; 4
babies due to severe encephalopathy, 2 due to severe persistent
pulmonary hypertension (PPHN) and 1 baby due to sepsis.
TABLE II Adverse Events During Cooling Period in Enrolled Neonates (N=103)
Persistent pulmonary hypertension of newborn
Sinus bradycardia (<80/min)
Sepsis (Culture positive or probable)
Acute kidney injury
Subcutaneous fat necrosis
In this study, we observed that cooling of
asphyxiated neonates using PCM-based cooling device can be done without
major complications in level 3 NICUs in India, with a well-defined
protocol in place. Most of the infants had a low temperature at the
initiation of cooling (35.2±1.3oC).
This might be a result of asphyxia or because of failure to switch on
warmer in asphyxiated babies (before initiation of TH) to prevent
inadvertent hyperthermia, which has been shown to worsen outcome in
these babies .
TH could be initiated within the 6 hours window
period in all the centers. The time taken to reach target temperature
(up to 120 minutes) in our study was higher than that in the NICHD trial
using servo-controlled equipment, where the target temperature was
reached in all babies within 90 minutes . The induction phase should
be as short as possible, as a longer time to reach the target
temperature delays the onset of TH. The core temperature of the neonates
in our study could be maintained within the target range during the
cooling phase in all the centers. The fluctuation (SD) of the
temperature during cooling phase (0.39ºC)
in our study was less when compared to the fluctuations reported by the
TOBY (0.5ºC) and NICHD (0.45ºC)
trials using servo-controlled systems [5,7].
While temperature readings <33ºC
increase the rate of complications of cooling, temperature >34ºC
would decrease the efficacy of TH. Hence maintaining the core
temperature within the target range is essential. In our study,
temperature readings outside the target range were higher as compared to
that seen in single-center study using the same PCM-based device (3.4%
and 1.4% respectively) . The temperature fluctuations beyond the
target range might be reduced with more intense nursing input to
maintain the target temperature and with experience. However, only 6
(5.8%) babies had temperature recorded <32ºC
compared to 10% in the NICHD study .
The study has some limitations. There was no control
group. The nursing interventions were not objectively measured. We did
not have follow-up data as we looked only at the feasibility and
Though the PCM-based device provides a stable
temperature during cooling, comparable to servo-controlled equipment,
the extent of nursing interventions required would be greater than while
using the automated equipment. The nursing input was not measured
systematically in our study. However, the nursing efforts required would
be less than while using frozen cool gel packs (FGP). In the study by
Bharadwaj, et al. , the FGPs needed to be changed once in 3-4
hours. Whereas while using the PCM, the FS-21 blocks may need to be
placed 2-3 times in 24 hours when temperature increases to 33.8oC
while the FS-29 do not need to be changed for the 72 hours cooling
period. Thus the two major drawbacks of low-cost cooling methods such as
FGP, water bottles and cooling fans namely the wider fluctuations of
target temperature and the labor-intensive nursing are less with the
PCM-based cooling device .
Most of the complications reported in cooled neonates
are likely to be due to the asphyxia per se rather than cooling.
In the recent Cochrane review , only thrombocytopenia and sinus
bradycardia were significantly higher in babies being cooled, compared
to non-cooled neonates. The complications in our study were much less as
compared to the TOBY trial . This could be due to fewer babies with
severe encephalopathy in our study (only 10% as compared to the 60% in
the TOBY trial). Three babies had subcutaneous fat necrosis in our
study, which was similar to the 2.8% reported in the Swiss Cooling
Registry . There was a high rate of discontinuation of cooling
before 72 hours in our study due to reasons such as hemodynamic
instability/ refractory shock, PPHN and bleeding. This was probably
because some of the centers were relatively inexperienced in TH and had
a low threshold to withdraw cooling.
Though our study shows that TH can be practiced
safely, adequate supportive care, continuous vitals monitoring and
monitoring of laboratory parameters are imperative during cooling. All
cooled neonates should preferably have central venous and arterial
lines. TH cannot be recommended in level 2 NICUs, as cooling without
adequate supportive care and back up of invasive ventilation may be
We conclude that therapeutic hypothermia of neonates
with HIE using PCM-based cooling device is feasible and safe when
practiced in level 3 NICUs in India. PCM-based device seems to be
comparable to standard servo-controlled equipment in maintaining the
Contributors: NT: concept, design, data
collection, data analysis, manuscript writing and review; AT, VB, MV,
SR, SW, LL, UB, SM, JM, AD, PYN and SN: design, data collection, data
analysis, manuscript writing and manuscript review; All authors approved
the final version.
Funding: The Miracradle-Neonate Cooler was
supplied by Pluss Advaced technologies free-of-cost to all the
participating centers. The workshop where the participants were trained
(including travel and accommodation) in using the Miracradle was funded
by Christian Medical College Vellore, Adit foundation and Indian
Overseas Bank (funds from the latter two raised by Pluss Advaned
technologies, the manufacturer of Miracradle).
Competing interests: NT was involved in the
concept and design of the Miracradle. None stated for other authors.
What is Already Known?
Phase Changing Material
(PCM)-based system is a low-cost technology that has recently
What This Study Adds?
Therapeutic hypothermia using PCM-based device is feasible
and safe when practiced in level 3 NICUs in India.
PCM-based device is comparable to standard servo-controlled
equipment in maintaining the target temperature.
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