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Year : 2021  |  Volume : 10  |  Issue : 1  |  Page : 24-30

Early clinical outcome and complications associated in neonates with hypoxic ischemic encephalopathy grade II/III who underwent treatment with servo controlled whole-body therapeutic hypothermia: A prospective observational study

Department of Neonatology, Indiana Hospital, Mangalore, Karnataka, India

Date of Submission25-Jul-2020
Date of Decision24-Aug-2020
Date of Acceptance10-Sep-2020
Date of Web Publication08-Feb-2021

Correspondence Address:
Dr. Abhishek K Phadke
Department of Neonatology, Indiana Hospital, Mangalore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_119_20

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Background: There are limited data regarding servo-controlled whole-body therapeutic hypothermia (TH) for neonates with hypoxic-ischemic encephalopathy (HIE) Stage II/III in the Indian setting. The objectives of this study were to determine the early clinical outcome of neonates with HIE Stage II/III treated with TH and to determine the mortality rate and associated complications. Methods: This study was a prospective observational study done at a Level 3A National Neonatology Forum accredited tertiary care neonatal intensive care unit (NICU). Term neonates with HIE Grade II/III admitted to NICU within 6 h of birth were enrolled in the study. Subjects underwent servo-controlled whole-body therapeutic cooling as per the research protocol. Results: Out of 54 subjects, 22 (40.7%) had stage II HIE and 32 (59.3%) had Stage III. The mortality rate was 24% (n = 13), with all having Stage 3. Direct breastfeeds was achieved in 65.9% of successfully cooled babies within 48 h after TH treatment. About 85.4% of babies who were successfully cooled had good early clinical outcomes as evidenced by good activity, normal tone, successful direct breastfeeding, and early discharge within 72 h post treatment with TH. Coagulopathy was observed in 70.4%, raised liver enzymes in 96.3% and thrombocytopenia in 9.3%. Conclusion: There is a significant correlation of grade of encephalopathy and blood gas abnormality at admission with the outcome in babies with HIE treated with TH. Majority of babies with HIE stage 2/3 who successfully completed TH had good early clinical outcomes at the time of discharge.

Keywords: Hypoxic-ischemic encephalopathy, neonatal hypoxic-ischemic encephalopathy, outcome, perinatal asphyxia, therapeutic hypothermia

How to cite this article:
Phadke AK, Kumble A, Ravikumar K. Early clinical outcome and complications associated in neonates with hypoxic ischemic encephalopathy grade II/III who underwent treatment with servo controlled whole-body therapeutic hypothermia: A prospective observational study. J Clin Neonatol 2021;10:24-30

How to cite this URL:
Phadke AK, Kumble A, Ravikumar K. Early clinical outcome and complications associated in neonates with hypoxic ischemic encephalopathy grade II/III who underwent treatment with servo controlled whole-body therapeutic hypothermia: A prospective observational study. J Clin Neonatol [serial online] 2021 [cited 2021 Aug 2];10:24-30. Available from: https://www.jcnonweb.com/text.asp?2021/10/1/24/308839

  Introduction Top

Hypoxic-ischemic encephalopathy (HIE) continues to be a major cause of neonatal mortality and morbidity globally. HIE related neonatal deaths occur in 1–3/1000 live births in high-income countries and up to 20/1000 live births in low and middle-income countries.[1] According to the National Health Mission 2017 statistics report from India, the neonatal mortality rate is 23/1000 live births, of which birth asphyxia accounts for nearly 12.9% of neonatal deaths.[2]

The pathophysiology involving neonatal HIE consists of multiple phases;[3] the first phase (0–6 h) results is changes in the vasculature. Primary energy failure sets in at the cellular level. Since there is a loss of oxygen that is readily available to the brain, cellular energy metabolism shifts to a dependency on anaerobic metabolism. This reliance on anaerobic metabolism pathways leads to the collection of lactic acid and depletion of adenosine triphosphate.[4] Secondary energy failure (6–48 h) follows, resulting in increased excitotoxicity, mitochondrial dysfunction, and oxidative stress resulting in significant damage to the neurons. To classify neonatal HIE and the degree of injury, the modified Sarnat 3 stage grading system is used and widely accepted. This system consists of three stages: mild, moderate, and severe, all based on clinical symptoms along with electroencephalogram evaluation.[5] A systematic review published by the Cochrane Library in 2013[6] concluded that 72 h of moderate hypothermia started within 6 h of birth reduces the rate of death and disability. Therapeutic hypothermia (TH) has a favorable effect on multiple pathways contributing to brain injury, including inhibition of excitatory amino acids,[7] altering the cerebral energy state,[8] cerebral blood flow and metabolism,[9] nitric oxide production,[7] and apoptosis.[10] It reduces extracellular levels of excitatory neurotransmitters and decreases brain glycine levels after ischemia.

Even though TH is the standard of care for neonates with HIE in developed countries, it is still in an early stage in our country. There is a paucity of published data from India on the outcomes of neonates treated with TH for HIE stage 2/3. There are various modalities for providing TH of which servo-controlled whole-body TH is the preferred method. In this study, we used servo-controlled automated device for instituting TH. The objectives of this study were to determine the early clinical outcome of neonates with HIE Stage II/III subjected to therapeutic cooling and to determine the mortality rate and associated complications.

  Methods Top

It was a prospective descriptive study done for 2 years from December 2016 to November 2018 at a Level 3A national neonatology forum accredited tertiary care neonatal intensive care unit (NICU). The hospital is accredited by the National Accreditation Board for Hospitals and Healthcare Providers and the National Board of Examinations, New Delhi. Our unit has in place since 2012, a structured protocol that records all perinatal risk factors and events in real-time and follows-up the babies periodically in the NICU and after discharge.

All infants of gestational age greater than or equal to 36 weeks, admitted to the NICU within 6 h of birth, were considered eligible for the study. The inclusion criteria had two components, as described below. At least 2 out of 3 physiological criteria and 1 out of 2 neurological criteria were required to be fulfilled to be included in the study.[11]

Physiological criteria

(i) Acute perinatal event– 10 min APGAR Score of ≤5. (ii) Needing assisted ventilation at birth continued for ≥5 min (positive pressure ventilation either bag and mask/tube and bag ventilation) or required mechanical ventilation. (iii) Metabolic acidosis or mixed acidosis with pH ≤7.1 and/or base deficit of ≥16 mmol/l in cord blood or any blood gas done within the 1st h of life.

Neurological criteria

(i) Presence of seizures (ii) Physical examination consistent with moderate to severe encephalopathy staged by modified Sarnat staging.[5]

At admission, if eligibility criteria, 2 physiological and 1 neurological criterion are met, whole-body cooling was initiated.[11] If eligibility criteria and 2 physiological criteria are met, but neurological criteria are not fulfilled, then cooling was not initiated. The baby was reassessed every 30 min for all neurological criteria until 6 h. If neurological criteria are fulfilled at any given time of assessment (<6 h of life), whole-body cooling was initiated.[12]

Babies with birth weight <2000 g, gestational age <36 weeks and inability to initiate whole-body cooling by 6 h of life were excluded from the study. Babies with life-threatening congenital abnormalities of the cardiovascular or respiratory systems like complex congenital heart disease (confirmed by Echocardiography) and anatomical disorders of the respiratory system (congenital diaphragmatic hernia, congenital cystic adenomatoid malformations, eventration of the diaphragm, esophageal atresia and tracheoesophageal fistula), major congenital malformations, imperforate anus, neuromuscular disorders, presence of lethal chromosomal anomalies confirmed by clinical examination at the time of admission were also excluded.[12]


We used an automated servo-controlled device, Tecotherm Neo™ (Inspiration healthcare) in our study. Eligible infants underwent whole-body cooling therapy to achieve and maintain core body temperature (rectal temp) at 33.5°C. Baby was nursed under strict aseptic conditions and management of airway, breathing, and circulation done as per standard protocol and infant requirements. Whole-body cooling was continued for the next 72 h after initiating the procedure. Central venous and arterial lines were inserted. Oral feeding was withheld during the procedure. Clinical monitoring details such as the level of consciousness, spontaneous activity, tone, primitive reflexes, heart rate, and respiration, were noted at admission and throughout the procedure. Laboratory testing of biochemical and hematological parameters such as complete blood count, blood culture, arterial blood gases, serum calcium, coagulation profile, and liver enzymes was done at admission/before starting the whole-body cooling.[13],[14] The reports are interpreted as per standard reference values.[15],[16] The laboratory tests are repeated as and when indicated. Rewarming was initiated after 72 h of whole-body cooling over a period of 7 h at the rate of 0.5°C per hour till core body temp of 37°C is reached.[11]

Babies who have successfully therapeutic cooling will be reassessed before discharge. Details regarding the establishment of feeding: Time taken for initiation of feeds, attainment of full feeds, and establishment of direct breastfeeds are noted. The duration of hospital stay after the completion of cooling was also noted. The presence of seizures and requirement of antiepileptic drugs for controlling seizures were observed. The requirement of anti-epileptic drugs was based on the severity of encephalopathy at admission, presence of seizures before cooling/during cooling, and persistence of seizures post cooling. Informed written consent was obtained from a parent after a full verbal and written explanation of the study. The attending physician was meeting the parents during the intervention period to ensure that they understand the study procedures and continue to consent to participate in the study.

Statistical analysis

Summary statistics were done by the mean, standard deviation (SD), and proportions. Inferential statistics were done by Chi-square test/Fisher's exact test and Mc-Nemar test. All measurements were done using SPSS 21.0 (IBM, Bangalore, India) software P < 0.05 was considered statistically significant.

  Results Top

Baseline characteristics

In our study, a total of 54 neonates satisfying the criteria for therapeutic cooling were enrolled. All the neonates included in our study were outborn. Majority of babies (n = 42, 77.8%) had birth weight appropriate for gestational age. Overall 55.6% (n = 30) were male and 44.2% (n = 24) were female. The mean age at the time of referral for neonates who were successfully cooled and discharged was 3.25 h (SD: 1.04) and for neonates who expired was 3.09 h (SD: 1.30). There was no statistical difference between the two.

In almost 3/4th of the babies (77.8%), there were no known/documented maternal risk factors for HIE in the neonate [Figure 1].
Figure 1: Maternal risk factors

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In almost 2/3rd of the subjects, there were no known/documented fetal risk factors for HIE [Table 1].
Table 1: Identifiable fetal risk factors

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Majority of the expired subjects (92.3%, n = 12) had abnormal pH and base excess as defined by pH < 7.1 or base excess < −16 at admission, in comparison with 56.1% (n = 23) of the successfully cooled subjects [Figure 2]. P value was significant (0.017).
Figure 2: Presence pH < 7.1 or Base excess < -16 at admission

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All the neonates who expired (100%, n = 13) had severe encephalopathy in comparison with 46.3% (n = 19) among the successfully cooled subjects [Figure 3]. P value was significant (0.017).
Figure 3: Degree of encephalopathy at admission (before initiation of cooling)

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Overall, 53% of the neonates had clinical seizures within 6 h of birth [Table 2]. P value was statistically significant (0.057).85.4% (n = 35) of the babies who were successfully cooled had normal activity, tone, and neonatal reflexes at the time of discharge [Table 3].
Table 2: Presence of seizures within 6 h after birth

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Table 3: Tone, neonatal reflexes, and activity in successfully cooled subjects assessed at the time of discharge

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All the babies who successfully completed cooling procedure were started on enteral feeds. The majority (65.9%, n = 27) of neonates reaches full feeds within 24 h of completion of cooling. Two babies (7.3%) went discharge against medical advice before attaining full feeds [Figure 4].
Figure 4: Time needed post therapeutic hypothermia treatment to attain full feeds in babies who were successfully cooled

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More than 3/4th (78.1%, n = 32) of the successfully cooled neonates were discharged within 5.5 days of admission, which includes 3.5 days of TH treatment [Figure 5].
Figure 5: Total duration of hospital stay (includes 3.5 days of therapeutic hypothermia treatment) in babies who were successfully cooled and discharged

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Three-fourth of the enrolled subjects (70.4%, n = 38) had coagulopathy during the procedure, 96.3% (n = 52) had raised liver enzymes and 9.3% (n = 5) had thrombocytopenia. There was no statistical difference between the mortality and successfully cooled/discharged subjects.

  Discussion Top

TH is generally regarded as one of the advanced and challenging procedures in neonatal care. It is the standard of care for neonates with perinatal asphyxia. Our study is mainly focused on short term early clinical outcomes to impress on the message as to how TH can help in reducing the overall morbidity in neonates who have suffered perinatal asphyxia.

Out of 54 subjects who were enrolled in the study, the mortality rate in our study was 24% (n = 13) as shown in [Chart 1]. All the 54 neonates enrolled in this study were outborn. This reflects the better quality of peripartum monitoring in tertiary care institutions, thereby contributing to reducing the incidence of HIE. However, in resource-restricted settings, brain damage due to perinatal asphyxia may be more established owing to maternal malnutrition, intra-uterine growth restriction, obstructed labor, and suboptimal obstetric/neonatal care. The usefulness of cooling may be reduced if there is a high incidence of preexisting brain damage or if the therapeutic window has elapsed.[17] According to the National Neonatal Perinatal Database report from India, the incidence of HIE is 1.4% among institutional deliveries and perinatal asphyxia accounts for 28.8% of neonatal deaths. However, this data may not reflect the real scenario and may represent only the tip of the iceberg as it represents the data of intramural births of only 18 centers. There is no accurate data on the number of neonates with HIE in India.[17]

The mean age at the time of admission of the referred neonates was 3.25 h for those were successfully discharged and 3.09 h for neonates who subsequently expired. The best time to start TH is within 6 h. However, TH was more effective in babies treated within the first 4 h of birth.[18] In almost 3/4th of the subjects in our study (77.8%), there were no known/documented maternal risk factors for HIE in the neonate [Figure 1]. Study done by Dr. Baliga et al.[19] showed that there is a need for improvements in documentation and reporting systems as a part of collective effort to reduce the neonatal mortality rate.

In our study, there was a statistically significant correlation of grade of encephalopathy and blood gas abnormality (as defined by pH <7.1 or base excess < −16 at admission) with the outcome. This is similar to the observation by Mannan et al.[20] that death was mostly observed in neonates who had a very high level of base deficit (>20 mmol/L) and very low pH (pH <7.0) in the 1st h postnatal arterial blood gas (ABG). This shows that despite early intervention and management, the outcome also depends on the severity/degree of encephalopathy before cooling. No babies were referred to us within 1 h after birth, and none had documentation of cord ABG/ABG in the immediate postnatal period or APGAR scores. Hence, the need for therapeutic cooling was based on the need for assisted ventilation and neurological criteria. Among the cases that we excluded in this study were few cases referred to us after 6 h of life, few even on day 2 with HIE, which may have benefitted from TH provided they were referred early. Similar observation was made by Bhat BV et al.[17] in their study on TH. Awareness and education regarding TH is the need of the hour.

Among the babies referred to us, 64.8% of babies had either ABG pH ≤7.1 or base excess < −16 despite the ABG being performed >1 h after birth. This again emphasizes on the need for cord ABG/ABG <1 h after birth to decide the need for TH. Study done by Prasanna et al.[21] showed that 35.5% of neonates with evidence of perinatal asphyxia had umbilical cord arterial pH <7. Out of the cases enrolled in our study, 53.7% of cases had seizures within 6 h of birth. 2.3% of neonates continued to have seizures post TH. All the neonates with seizures were discharged home on antiepileptic being instructed to be on regular follow-up. Gano et al.[22] showed in their study that TH significantly reduces the severity and the duration of seizures in neonates with HIE.[22]

We observed that 85.4% (n = 35) of the babies who were successfully cooled had normal activity, tone, and neonatal reflexes at the time of discharge. This is similar to the study by Massaro et al.[23] wherein around 3/4th of the enrolled subjects had normal activity before discharge. All babies who successfully completed TH were initiated on feeds immediately. Out of these, 65.9% (n = 27) babies attained full feeds and direct breastfeeds were achieved within 4.5 days of admission, which includes 3.5 days of TH treatment. The study by Massaro et al.[23] showed similar results, with 85% of the cooled babies reaching complete feeds before discharge. About 82.9% of cases were discharged within 72 h of completion of cooling. This shows contrary to the general belief that TH prolongs the duration of hospital stay; TH reduces the duration of hospital stay and morbidity associated with the disease. It reduces the long-term disease burden on the family and society. The duration of NICU stay in the enrolled subjects were almost similar to the results found in the randomized study of Shankaran et al.[12]

More than 3/4th of the enrolled subjects (70.4%) had coagulopathy during the procedure [Table 4]. However, none had clinical bleeding and only a few of them required fresh frozen plasma transfusions. The majority (96.3%) had raised liver enzymes. Thrombocytopenia was seen in only 9.3% of the subjects. Our study showed a higher incidence of the coagulopathy in comparison to a study done by Sinha R et al.[24] This could be partly due the different and newborn specific cutoffs that were used in our study.[15]
Table 4: Coagulopathy, raised liver enzymes, and thrombocytopenia during therapeutic cooling

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Our study had few limitations; one among them was the absence of an amplitude-integrated electroencephalogram for the diagnosis of electrical seizures. We looked only at the early clinical outcomes at the time of discharge, which may not directly correlate with the long-term outcome.

  Conclusion Top

Our study shows that there is a significant correlation of grade of encephalopathy and blood gas abnormality at admission with the outcome in babies with HIE following treatment with TH. Majority of babies with HIE stage 2/3 who successfully completed TH had good early clinical outcomes at the time of discharge, thereby reducing mortality and morbidity burden. These babies are more likely to be successfully discharged early from the hospital on direct breastfeeding. This is very reassuring and has a good prognostic implication.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2], [Table 3], [Table 4]


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