The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Does therapeutic hypothermia reduce acute

kidney injury among term neonates with perinatal
asphyxia? – a randomized controlled trial

Vasanthan Tanigasalam, Vishnu Bhat, Bethou Adhisivam & M. G. Sridhar

To cite this article: Vasanthan Tanigasalam, Vishnu Bhat, Bethou Adhisivam & M. G. Sridhar
(2015): Does therapeutic hypothermia reduce acute kidney injury among term neonates with
perinatal asphyxia? – a randomized controlled trial, The Journal of Maternal-Fetal & Neonatal
Medicine, DOI: 10.3109/14767058.2015.1094785

To link to this article: http://dx.doi.org/10.3109/14767058.2015.1094785

Published online: 12 Oct 2015.

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ISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, Early Online: 1–4

! 2015 Taylor & Francis. DOI: 10.3109/14767058.2015.1094785

ORIGINAL ARTICLE

Does therapeutic hypothermia reduce acute kidney injury among term

neonates with perinatal asphyxia? – a randomized controlled trial
Vasanthan Tanigasalam1, Vishnu Bhat1, Bethou Adhisivam1, and M. G. Sridhar2
1
Department of Neonatology and 2Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER),
Pondicherry, India
Downloaded by [Deakin University Library] at 03:21 16 October 2015

Abstract Keywords
Objective: The objective of this study is to evaluate whether therapeutic hypothermia reduces Acute kidney injury, AKI, neonate, perinatal
the incidence of acute kidney injury (AKI) among term neonates perinatal asphyxia. asphyxia, therapeutic hypothermia
Methods: This randomized controlled trial conducted in a tertiary care teaching hospital, south
India included 120 term neonates with perinatal asphyxia who were randomized to receive History
either therapeutic hypothermia or standard supportive care. Renal parameters of neonates in
both the groups were monitored and AKI was ascertained as per Acute Kidney Injury Network Received 20 January 2015
criteria. Revised 13 September 2015
Results: The incidence of AKI was less in therapeutic hypothermia group compared to standard Accepted 13 September 2015
treatment group (32% versus 60%, p50.05). The incidence of Stages 1, 2, and 3 AKI was 22%, Published online 9 October 2015
5%, and 5% in therapeutic hypothermia group compared with 52%, 5%, and 3%, respectively, in
the standard treatment group. The mortality was less in therapeutic hypothermia group
compared with the standard treatment group (26% versus 50%, p50.05).
Conclusion: Therapeutic hypothermia reduces the incidence and severity of AKI among term
neonates with perinatal asphyxia.

Introduction south India from October 2013 to October 2015 after due
approval from the Institute Ethical Committee. The study was
Hypoxic ischemic encephalopathy (HIE) continues to be a
also registered in the Clinical Trials Registry of India (CTRI/
major cause of neonatal mortality and morbidity across the
2013/10/004053). Term neonates with HIE were included in
globe. HIE occurs in 1–3 per 1000 live births in high income
the study if they had encephalopathy (Sarnat and Sarnat
countries, and up to 20 per 1000 live births in low and middle-
staging), pH 7 or base deficit 12 meq in cord blood and
income countries [1]. According to National Neonatal
fulfilling any two of the following criteria: (a) Apgar at
Perinatal Database (NNPD) report from India, perinatal
10 min of life 5, (b) evidence of fetal distress, (c) assisted
asphyxia accounts for 28.8% of neonatal deaths [2]. Renal
ventilation for at least 10 min after birth, (d) evidence of any
injury is the most common organ dysfunction in perinatal
organ dysfunction. Neonates more than 6 h of age at the time
asphyxia occurring in 40–50% cases [3]. There is inadequate
of randomization, extramural neonates, and those with major
data to evaluate the effectiveness of therapeutic hypothermia
congenital abnormalities, absence of spontaneous respiratory
on acute kidney injury (AKI) among term neonates with
efforts by 20 min after birth or history of maternal renal
perinatal asphyxia. Although therapeutic hypothermia has
failure were excluded [5]. After obtaining informed written
been established as standard of care for term babies with
consent from parents, neonates were randomized into two
perinatal asphyxia in developed countries, it is yet to gain
groups (Therapeutic hypothermia or standard treatment) using
momentum in low and middle income countries like India [4].
computer-generated random numbers. Allocation conceal-
There exists a clinical equipoise on this issue in our setting
ment was done using opaque-sealed envelopes. The demo-
and hence this Randomized Controlled Trial (RCT).
graphic parameters of mother, significant antenatal problems,
Material and methods and other clinical data including gestational age, birth weight,
Apgar scores and resuscitation details were recorded.
This RCT was conducted in the Neonatology department of Whole body therapeutic hypothermia was applied using
JIPMER, Pondicherry a tertiary care teaching hospital of cool gel packs in the intervention arm. The warmer was
switched off and two or three cloth-covered gel packs were
placed over the sides of chest, abdomen, back, head, and
Address for correspondence: Dr. Vishnu Bhat, Senior Professor and
axilla of the neonate. These plastic packs containing gel
Head, Department of Pediatrics & Division of Neonatology, JIPMER,
Pondicherry 605 006, India. E-mail: drvishnubhat@yahoo.com material used for storing vaccines were pre-refrigerated
 2 V. Tanigasalam et al. J Matern Fetal Neonatal Med, Early Online: 1–4

Enrollment Assessed for eligibility (n=150)

Excluded (n= 30)

♦ Not meeting inclusion criteria (n=25)
♦ Declined to participate (n=5)

Randomized (n=120)

Group A
Allocaon
Allocated to therapeutic hypothermia (n=60)
♦ Received allocated intervention (n=60)
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Group B
Allocated to standard treatment (n=60)
♦ Received standard treatment (n=60)

Clinical course
AKI 32% (n =19) AKI 60% (n =36)
Mortality 26% (n= 16) Mortality 50% (n=30)

Analysis
Analysed (n=60) Analysed (n=60)
♦ Excluded from analysis (n=0) ♦ Excluded from analysis (n=0)

Figure 1. CONSORT flow diagram.

at 4  C before use. Each neonate on an average required four
gel packs to complete cooling. A target temperature of 33–
34  C was maintained by continuous rectal and skin tempera-
ture monitoring every 15 min for the first 4 h and every
second hour for the next 68 h. During cooling period, if the
neonate was overcooled, then gel packs were removed one by
one and if temperature increased 434  C, then fresh cooling
gel packs were replaced for old ones to maintain target rectal
temperature. Close monitoring was done by well-trained
dedicated nursing staff. Vital parameters were recorded
throughout and at the end of 72 h, cooling gel packs were
removed one by one and radiant warmer was turned on to
raise the body temperature by 0.5  C/h to reach the target
temperature of 36.5  C over next 6 h. Environmental
temperature of the NICU was usually 28–29  C. Neonates in
the standard treatment group were treated as per the NICU
protocol for HIE, maintaining rectal temperature at 36.5  C by
keeping them under the warmer in the servo-controlled mode
[5]. Infants in both the groups were monitored carefully for
adverse events in the first 72 h like shock, bleeding and
coagulopathy, arrhythmias, skin changes and renal failure.
Apart from therapeutic hypothermia, neonates in both groups
received similar supportive care including anticonvulsants,
inotropes, and mechanical ventilation as per standard NICU
protocol.
Blood urea, serum creatinine, and electrolytes were
estimated for all infants at 6 h, 36 h, and 72 h in both the
groups. Paired urine samples were collected at 6 h, 36 h, and
72 h for measuring urine sodium and creatinine from which
fractional excretion of sodium was calculated. Neonates with
raising creatinine values were classified into three stages of
acute kidney injury based on the Acute Kidney Injury
Network (AKIN) criteria. The following definitions were
used in AKI staging: Stage 1 AKI – increase in serum
creatinine40.3 mg/dl or Serum creatinine4150–200% from
baseline, Stage 2 AKI – increase in serum creatinine
4200–300% from baseline, and Stage 3 AKI – increase in
serum creatinine4300% from baseline or serum creatinine
44.0 mg/dl with an acute rise of at least 0.5 mg/dl [6,7]. The
incidence and the severity of AKI calculated at end of 96 h in
both the groups. In case of neonates who died within 96 h of
life, the severity of AKI was calculated at the time of death.
Neonates with AKI were uniformly managed as per NICU
protocol including fluid restriction and dose adjustment of
nephrotoxic medications. Those neonates with persistent
elevation in creatinine, low urine output, fluid overload
features, and hyperkalemia despite medical management
underwent peritoneal dialysis. Mortality and short-term
outcome were assessed till discharge.
As previous studies comparing renal function in newborns
with perinatal asphyxia treated with hypothermia were not
available, sample size was collected based on the studies
which showed changes due to hypothermia in DNA damage
and oxidative stress [8]. The sample size was calculated using
 DOI: 10.3109/14767058.2015.1094785 AKI in perinatal asphyxia 3
Table 1. Baseline parameters of the two groups. Table. 3. Renal function parameters – therapeutic hypothermia versus
standard treatment (repeated measures ANOVA).
Therapeutic Standard
hypothermia treatment p Therapeutic Standard
Characteristics group (n ¼ 60) group (n ¼ 60) values hypothermia treatment
Characteristics group (n ¼ 60) group (n ¼ 60)
Mother’s age 24.61 ± 3.03 24.80 ± 2.62 0.74
Primigravida 27 (45%) 36 (60%) Serum creatinine
Intrapartum complications 56 h 1.15 ± 0.31 1.12 ± 0.223
Fetal distress 39 (65%) 39 (65%) 40.05 36 h 1.13 ± 0.33 1.23 ± 0.273
Meconium stained liqor 26 (43%) 37 (62%) 40.05 72 h 1.195 ± 0.55 1.34 ± 0.524
Mode of delivery p Values 0.78 0.002
Spontaneous vaginal 18 (30%) 19 (32%) 40.05 Fractional excretion of sodium
Instrumental 18 (30%) 18 (30%) 40.05 56 h 2.81 ± 2.53 1.68 ± 2.05
Caesarean section 24 (40%) 23 (38%) 40.05 36 h 3.98 ± 3.81 4.75 ± 4.06
Gestational age (days) 277 ± 9.19 280 ± 16.6 0.29 72 h 4.57 ± 4.58 6.554 ± 5.2
Birth weight (kg) 2.69 ± 0.34 2.76 ± 0.297 0.21 p Values 0.003 50.001
Apgar at 10 min 5 (3–6) 5 (3–6)
(median)
Encephalopathy
(Sarnat’s staging) carried out at 5% level of significance and p values50.05 was
Stage 1 1 (2%) 4 (7%) 40.05 considered as significant.
Stage 2 42 (70%) 41 (68%)
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Stage 3 17 (28%) 15 (25%)

Cord blood pH 6.95 ± 0.22 6.93 ± 0.14 0.55 Results
Base excess(cord blood) 16.12 ± 2.93 16.18 ± 0.30 0.87
Anticonvulsants needed 77% 87% 40.05 The consort flow chart of the RCT is depicted in Figure 1.
Inotropic support needed 42 (70%) 46 (77%) 0.41 The baseline parameters between the two groups were
NEC 12 (20%) 12 (20%) 1.0 comparable (Table 1). The liver enzymes and hematological
PPHN 3 (5%) 6 (10%) 0.3
parameters were similar in both groups. The mean rectal
temperature in therapeutic hypothermia group was
33.7  C ± 0.5  C, whereas in standard treatment group, it
was 36.8  C ± 0.4  C. Nineteen (31%) neonates in Therapeutic
Table 2. Renal function parameters – therapeutic hypothermia versus
standard treatment. hypothermia group and 36 (60%) newborns in the standard
treatment group developed AKI. Neonates in the therapeutic
Therapeutic Standard hypothermia group who developed Stage 1, Stage 2, and Stage
hypothermia treatment 3 AKI were 13 (22%), 3 (5%), and 3 (5%), respectively. But in
group (n¼60) group (n¼60) p values the standard treatment group, neonates who developed Stage
S. creatinine 1, Stage 2, and Stage 3 AKI were 31 (52%), 3 (5%), and 2
56 h 1.15 ± 0.31 1.12 ± 0.223 0.010 (3%), respectively. The incidence of AKI was less in the
36 h 1.13 ± 0.33 1.23 ± 0.273
72 h 1.195 ± 0.55 1.34 ± 0.524
therapeutic hypothermia group compared with the standard
Median change 0.00 0.3 treatment group (32% versus 60%, p50.05, OR 3.23). The
over 72 h (1.3 to 2.0) (0.8 to 2.2) renal function parameters in both the groups are described in
FeNa Table 2. The trend in change in serum creatinine over 72 h
56 h 2.81 ± 2.53 1.68 ± 2.05 50.05
36 h 3.98 ± 3.81 4.75 ± 4.06
was significant in the standard treatment group when
72 h 4.57 ± 4.58 6.554 ± 5.2 compared with the therapeutic hypothermia group. But the
Median change 0.2 (1.1 to 13) 4.05 (4 to 15.9) trend in change in Fractional excretion of sodium was
over 72 h significant in both the groups (Table 3). Peritoneal dialysis
was done in two neonates in the hypothermia group and one
in the standard treatment group. The mortality was less in the
therapeutic hypothermia group compared with the standard
the formula for the sample size testing of two means by treatment group (26% versus 50%, p50.05). Most deaths in
assuming a mean difference of 30 with 80% power and 5% both the groups occurred within 5 d of life. These newborns
alpha error. Assuming a dropout rate of 20%, 60 neonates had had features of severe encephalopathy and refractory seizures
to be recruited in each group. Statistical analysis was done requiring more than three anticonvulsants to control seizures.
using SPSS version 19.0 (SPSS Inc., Chicago, IL). Data were The mean developmental age at 6 months of age was 5.53
analyzed using both descriptive and inferential statistics. The months in the therapeutic hypothermia group whereas it was
continuous parameters were expressed as mean with standard 4.60 months in the standard treatment group. The mean
deviation while categorical data were expressed as frequen- developmental quotient in the therapeutic hypothermia and
cies and percentages. The comparison of the distribution of the standard treatment group was 91.97% and 76.44%,
categorical data between the groups was done using the Chi- respectively.
square or the Fishers exact test. The mean between the groups
was compared by using independent Student’s t-test or Mann–
Discussion
Whitney’s test. Repeated measures of ANOVA were used to
assess the statistical significance of the difference in Neonates with perinatal asphyxia are at risk for multiorgan
continuous parameters over time. All statistical analysis was dysfunction after birth. Kidney injury often follows perinatal
 4 V. Tanigasalam et al.
asphyxia, as blood is shunted toward vital organs. Previous
studies have reported a broad range of incidence of AKI after
perinatal asphyxia, with rates as high as 72% in neonates with
severe perinatal asphyxia [9–11]. The incidence of AKI in our
study is comparable with an earlier study by Gupta et al. but
lesser than that observed by Aggarwal, Karlowicz, and Jayom
Karlo et al. [12–15]. This may be due to variable definition of
AKI across studies. Our study proves that earlier recognition
of AKI is possible using the AKIN criteria which can
indirectly improve the outcome of neonates with perinatal
asphyxia. The trend of serum craeatinine and FeNa observed
in this RCT are similar to reports published [12–15].
Selewski et al. [11] have observed in a retrospective study
that the incidence of AKI remained high in neonates with
perinatal asphyxia, but lower than rates published before the
advent of therapeutic hypothermia. Although our study design
was different, the incidence of AKI was less in the therapeutic
hypothermia group compared with the standard treatment
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group. Stage 1 AKI was more common in both the groups.
Early detection and appropriate management of these neo-
nates probably prevented them progressing to severe AKI.
Neonates in the standard treatment group had three times
higher risk of death compared with the hypothermia group.
Early studies evaluating AKI in newborns with perinatal
asphyxia reported mortality rates as high as 61% in those with
AKI [11,16]. Improvements in the care of newborns with
perinatal asphyxia have led to a significant decrease in overall
mortality.
A meta-analysis by Pauliah et al. which included seven
trials, comprising a total of 567 infants showed that cooling
therapy was not associated with a statistically significant
reduction in neonatal mortality in low- and middle-income
countries although the confidence intervals were wide and not
incompatible with results seen in high-income countries. The
apparent lack of treatment effect may be due to the
heterogeneity and poor quality of the included studies,
inefficiency of the low technology cooling devices, lack of
optimal neonatal intensive care, sedation and ventilatory
support, overuse of oxygen, or may be due to the intrinsic
difference in the population, for example, higher rates of
perinatal infection, obstructed labor, intrauterine growth
retardation, and maternal malnutrition [1].
In a term neonate with perinatal asphyxia, the insult to the
brain is usually obvious by the clinical features like sensor-
ium, seizures, and tone. However, renal dysfunction and AKI
can be missed if the renal parameters are not monitored.
Hence, the focus is to preserve renal function in addition to
cerebral protective strategies in neonates with perinatal
asphyxia. It is indeed interesting that therapeutic
J Matern Fetal Neonatal Med, Early Online: 1–4
hypothermia, primarily a neuroprotective strategy also
improves renal function in the affected neonates and hence
this RCT gains importance. However, the common mechan-
isms by which therapeutic hypothermia benefits the brain and
the kidneys need to be explored.
Declaration of interest
The authors report that they have no conflicts of interest.
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