Introduction

Hypoxic ischemic encephalopathy (HIE) continues to be a major cause of neonatal mortality and morbidity across the globe. HIE occurs in 1 to 3 per 1,000 live births in high-income countries, and up to 20 per 1,000 live births in low and middle-income countries [1]. According to National Neonatal Perinatal Database (NNPD) report from India, incidence of HIE is 1.4 % among institutional deliveries and perinatal asphyxia accounts for 28.8 % of neonatal deaths [2]. 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 number of neonates with HIE in India. Despite intense efforts of reducing HIE through training in neonatal resuscitation [3] it remains a major cause of neonatal morbidity with obvious influence on their long term neurodevelopmental outcome. The management of HIE is currently limited to supportive intensive care. Therapeutic hypothermia (TH) has been proven to be effective in reducing morbidity associated with HIE and has become the standard of care for HIE in developed countries [4]. However in underdeveloped and transitional countries where the problem is more common, therapeutic cooling is still in the nascent phase. There are several reasons for this problem in resource restricted settings.

Similarly, despite availability of compelling clinical evidence that moderate cerebral hypothermia initiated within a few hours after severe hypoxic insult can reduce subsequent neuronal loss and improve behavioral recovery in term infants, implementing the same in resource restricted settings of India is not that easy mainly because of the expensive devices used for providing TH in published studies from developed countries. Recently, two systematic reviews on the efficacy and safety of TH in low-and-middle-income resource settings have been published [1, 5]. The systematic review by Pauliah et al. did not find any statistically significant reduction in neonatal mortality in low-and middle-income countries although the confidence intervals were wide [1]. Galvao et al. observed that there is enough evidence to support hypothermia as the standard care for HIE but evidence from low-resource settings is limited [5]. In the present article authors report their own experience of 4 y of low cost innovative approach to initiating TH at their institution (JIPMER) Pondicherry and review the literature from other investigators in India working in this field in similar situation.

Pathophysiology of HIE and Therapeutic Cooling

Though asphyxia can affect all organ systems of the body, the resulting neuronal damage is often permanent and hence a matter of concern. HIE, the pathognomonic clinical syndrome of asphyxial neuronal insult occurs in 50–60 % of babies with perinatal asphyxia [6, 7]. HIE is not a single ‘event’ but is rather a continuing process over a period starting from the time of insult. Two distinct episodes of neuronal impairment are known to occur during this time. The immediate (primary) hypoxic insult is followed by a latent period of recovery which lasts for almost six hours. Subsequently, there is a longer and profound period of secondary neuronal damage due to the release of chemical mediators. Neural tissue may die initially during the actual ischemic or asphyxial event. Several neurons however recover, at least partially, from the primary insult in the ‘latent’ phase but die hours or even days later (secondary or delayed cell death) (Fig. 1).

Fig. 1
figure 1

Stages of neuronal injury in HIE

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Mechanisms that have been related to the latent phase include suppression of programmed cell death (‘apoptosis’), inflammation and the extrinsic cell death pathway and abnormal receptor activity. Reduction of cerebral metabolism, suppression of cytotoxic edema and moderation of seizure intensity are some proposed mechanisms by which TH is useful in HIE. Suppressing free radical production and excitotoxin release contribute to protection when cooling is initiated during hypoxia-ischemia or reperfusion [8–11].

Therapeutic Hypothermia Trials for HIE in India

So far there are seven published reports of TH for HIE from India. An overview of their details is summarized in Table 1. Whole body cooling using frozen gel packs have been used in all studies except in one by Thayyil et al. [19]. In the developed countries, body wraps and mattresses are used for whole body cooling (Blanketerol III, Tecotherm TS med 200, MTRE CritiCool, Tecotherm-Servo) and Cool cap for selective head cooling. All the Indian studies have utilized low cost cooling devices with significant outcome.

Table 1 TH trials in India for HIE
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Authors’ Experience at JIPMER

TH trials for HIE have been conducted in JIPMER, Pondicherry since 2009. In a report of an RCT by Bharadwaj et al. [12], authors showed that TH group had a significant reduction in the combined rate of death or developmental delay at 6 mo of age. Term neonates with HIE were subjected to TH using cooling gel packs. These packs were made of plastic and contained cooling gel material used to store the vaccines. Out of 160 neonates screened, 130 neonates were eligible as the sample size for the study, of which 124 babies completed the study. Fifty-four babies in TH group and 53 in the control group were finally followed up to 6 mo of age. There were no significant differences in the adverse events or complications between the two groups. All the babies could be cooled using cooling gel packs, and the mean rectal temperature (SD) was 33.7 +/−1.02 °C. Mean duration to reach the target rectal temperature after initiation of cooling was 2 h. Babies in the TH group had a significantly better neurological status at discharge based on Amiel-Tison examination [20] (84 %) compared to the control group (60 %) (p < 0.05; RR: 0.4, 95 % CI: 0.21–0.76). The death rate for the babies in the TH group was lower (4.8 %) compared to 9.7 % in the control group (p > 0.05; RR: 0.5, 95 % CI: 0.13–1.91). It was also observed that the developmental delay at 6 mo for the babies in the TH group was significantly lower (p < 0.05; RR: 0.17, 95 % CI: 0.04–0.71) (3.7 %) as compared to the control group (22.7 %), while combined death and developmental delay was 8.1 % in the TH group compared to 29 % in the control group (p < 0.05; RR: 0.28, 95 % CI: 0.11–0.70). Based on Baroda Developmental Screening Test, mean developmental score, developmental age and quotient were higher in the TH group than the control at 6 mo of age [12].

In an another RCT from JIPMER by Joy et al., [13] after 72 h of TH, total antioxidant status (TAS) was significantly higher (p = < 0.001) (761.69 ± 114.01 vs. 684.16 ± 88.86) and malondialdehyde (MDA) was significantly lower (p = < 0.001) in TH group (1.73 ± 0.66 vs. 5.2 ± 1.06). MDA is the product of the lipid peroxidation secondary to the free radicals attack on the polyunsaturated fatty acids of cells and TAS denotes total antioxidant activity as a whole. The risk of developing neurodeficit was lower (p < 0.001) in TH group with relative risk of 0.49 and 95 % confidence interval: 0.29–0.68. The frequency of clinically observed seizure activity and the number of antiepileptics needed to control the seizure activity were significantly lower in TH group when compared to control group. There was one death in hypothermia group compared to four deaths in control group. Based on ROC curve, the MDA value of 1.95 μmol/L at 72 h of age was found to have 98.5 % sensitivity and 70 % specificity for predicting neurological deficit at discharge. This study concluded that TH reduces oxidative stress in term babies with perinatal asphyxia and is associated with better neurological outcome and reduction in the oxidative stress could be an important mechanism by which TH works in HIE [13].

The authors also demonstrated that birth asphyxia has been documented to cause DNA damage by comet assay [21]. Whether TH reduces this DNA damage is an interesting question. Another RCT was conducted in authors’ center to study the effect of TH on oxidative stress-induced DNA damage and neurodevelopmental outcome among term neonates with perinatal asphyxia by Gane et al. Term neonates with birth asphyxia were randomized into the TH group or control group. Blood sample was collected before starting TH, at 36 h, and after completion of TH (at 72 h) for DNA damage and oxidative stress assessment using comet assay, 8-hydroxy2-deoxyguanosine (8-HDG), and total antioxidant status. Infants were followed up to 18 mo and neurodevelopmental assessment was conducted using the Developmental Assessment Scale for Indian Infants (DASII). After 72 h, the TH group showed lower comet tail movement (12.88 ± 2.14) than the control group (22.16 ± 5.26) (p < 0.05). 8-HDG levels increased significantly in the control group (1252.87 ± 357.07) as compared to the hypothermia group (757.03 ± 198.49) (p < 0.05). Neurodevelopmental assessment at 18 mo showed significantly low motor and mental developmental quotient in the control than in the hypothermia group. This study concluded that TH reduced oxidative stress-induced DNA damage and improved neurodevelopmental outcome at 18 mo in perinatal asphyxia [14].

These JIPMER trials have shown that TH is possible in resource limited settings and that TH leads to reduction in oxidative stress and DNA damage due to perinatal asphyxia. More importantly the neurological outcome was found to be better with TH. Thus, the benefits of TH using simple low cost devices in infants with HIE in the Indian and other developing countries cannot be overemphasized.

Vellore Experience

Similar studies using Gel packs in treating HIE were conducted at Christian Medical College, Vellore. Thomas et al. showed that whole body cooling is feasible and safe in a low resource setting and can be achieved with minimal additional cost using cooling gel packs [15]. In their study the mean time taken to achieve target rectal temperature was 52 ± 25 min. The mean rectal temperature during cooling was 32.9 ± 0.11 °C. The target temperature could be maintained for 72 h without difficulty in all 20 babies. Adverse events observed during cooling were thrombocytopenia (25 %), sinus bradycardia (25 %), deranged bleeding parameters (20 %), aposteatonecrosis (15 %), hyperglycemia (15 %), hypoglycemia (10 %), hypoxemia (5 %), life-threatening coagulopathy (5 %) and death (5 %). Shivering was noted in many of the babies, especially in the initial phase of cooling [15].

Kashmir Experience

A study from Kashmir by Bhat et al. included 20 neonates with severe perinatal asphyxia who received whole body TH and 15 neonates who served as controls. Although there were no significant differences between the patients who died in the two groups (15 % vs. 33 %, p > 0.05), treated neonates were found to have lower abnormal neurological examination at discharge (p < 0.001) [18].

Kerala Experience

Thayyil and co-workers have observed that TH did not reduce the brain injury apparent on MR imaging in a small trial from Calicut [17]. They reported the results of their trial on therapeutic whole-body cooling using Phase changing material (PCM). It is made of salt hydride, fatty acid, and esters or paraffin, and melt at a set point; in the process it can store or release large amounts of energy. Thirty three infants with neonatal encephalopathy (Thompsons encephalopathy score > 5) [19] aged < 6 h were included. The median cooling induction time was 30 min and rewarming took 10.3 h at a rate of 0.24 (0.2–0.4)°C/h. Clinical seizures were noted in seven (44 %) standard-care and eight (47 %) cooled infants. Two (13 %) standard-care and four (24 %) cooled infants died; the neurological examination at discharge was abnormal in six (43 %) standard care and eight (62 %) cooled infants. PCM cooling was effective only when the ambient temperature was < 28 °C, and required close temperature monitoring by the nursing staff. PCM use may reduce frequent temperature fluctuations and it is less cumbersome. PCM may be an effective, low technology cooling device suitable for use in neonatal units of some low and middle-income countries. This study was not powered to examine any clinical outcomes, and they concluded that further evidence from large clinical trials are required before cooling is offered as a therapy for neonatal encephalopathy. One such multi-country trial (HELIX—Hypothermia for Encephalopathy in Low Income Countries) is expected to start recruiting in the near future [19–22].

Problems in Instituting Therapeutic Hypothermia in India

In a review on ethical and practical issues relating to the global use of TH for perinatal encephalopathy, Wilkinson et al. have summarized the following points which are pertinent to Indian scenario also [23]. 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. More than two third of the deliveries in India happen outside the hospital [24]. The usefulness of cooling may be reduced if there is a high incidence of pre-existing brain damage or if the therapeutic window has elapsed. By the time the neonates are admitted in the neonatal unit, the secondary surge of neuronal death related to secondary energy failure may have already happened [25].

In several areas, HIV infection and puerperal sepsis are relatively common among mothers. Perinatal asphyxia may also co-exist with neonatal sepsis, and it may be challenging to differentiate both the conditions at birth. Exclusion of infected infants is unlikely to be realistic and core temperature reduction may result in neutrophil compromise, which can worsen sepsis and pneumonia. This may partially explain the relationship between hypothermia and neonatal death in developing countries [26–29]. Most of the earlier trials included sick neonates needing multi-organ support [30, 31]. Such neonates may not survive in a low-resource setting. Hence, it is possible that hypothermia may be less effective in a different population of patients. On the contrary, even neonates with milder encephalopathy may be at a high risk of adverse neurodevelopmental outcome [32]. Moreover, it is possible that mild disabilities may affect the quality of life and survival more directly than in the developed countries and lead to significant socioeconomic burden. Therefore, the risk /benefits of cooling in developing countries are likely to be altered.

Accidental hypothermia is witnessed in many asphyxiated infants in developing countries due to a number of factors including home birth, lack of basic neonatal care and overhead radiant warmers [29]. Accidental hypothermia must be differentiated from TH and may dilute the benefit of TH in the standard care group in clinical research. Excessive cooling or ‘overcooling’ is commonly associated with ‘inadequately controlled’ cooling which usually happens during transport of very ill asphyxiated infants. In low-resource settings, the mandatory measuring of core body temperature may not always be practical when practicing TH. If a standardized measurement of skin temperature could replace core temperature monitoring, it would make cooling more feasible. Another study by Niranjan et al. which analyzed a total of 3,224 paired rectal and skin temperature measurements in 40 babies who underwent TH for HIE concluded that skin temperature could not be used instead of rectal temperature when practicing TH for HIE. Though the ‘zero heat flow’ method was superior to the axillary method of skin temperature monitoring, it could not be used as a surrogate for rectal temperature when cooling babies with HIE [16].

Pre requisites for Initiating TH

Strict guidelines and adequate supervision are essential for implementing TH for HIE. Monitoring facilities of the NICU, trained personnel and a back up system to manage complications should be in place. Inadvertent or accidental excessive hypothermia should be a “never event” in the NICU. The minimum prerequisites (4Ps) for an optimum TH implementation are described in Table 2.

Table 2 Pre requisites for an optimum TH implementation
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Cost of Therapeutic Hypothermia Using Innovative Methods

JIPMER and CMC, Vellore have utilized reusable ice gel packs obtained from the immunization clinics at no added expense. The only additional cost involved was the cost of the reusable rectal probes (Rs 900/probe). Several other researchers have used cold water/ ice gel packs in previous studies either for head cooling or for inducing whole body hypothermia [33–35]. Compared to this, the standard equipment used in cooling is expensive: the cooling mattress costs Rs 500,000 while the cool cap costs Rs 3,500,000. Robertson et al. [36] used water bottles filled with cool tap water, and Horn et al. [37] devised a servo controlled fan to maintain hypothermia. The Indian experience indicates that cooling is possible in a low resource settings and can be made inexpensive by innovative means.

Ethical Challenges

The implementation of TH in resource restricted settings like India is associated with a number of ethical issues [38, 39]. These issues relate particularly to the transition from experimental therapy to practice and the extrapolation of research evidence to clinical care are a matter of concern. It may not be acceptable or safe to extrapolate evidence from trials performed in developed countries to underdeveloped and transitional countries [40]. There are differences in the epidemiology and outcome of HIE in low-resource settings [32]. For example, infants may have had a longer time since brain injury because of obstructed labor or out-of hospital delivery. There is a high incidence of bacterial sepsis and pneumonia in encephalopathic infants in India [26]. Many of the more severely affected infants who require respiratory support and who were enroled in previous trials would not survive in a transitional country setting. These differences, and others, could alter the safety or effectiveness of TH.

Given the possibility that the new treatment would, in fact, cause harm, some have recommended that TH should not be adopted in India except in controlled trials, citing the ethical principle of non-maleficence [41]. Before TH is introduced, the NICU should meet highest standards of level III care as recommended by National Neonatology Forum (NNF). Only under such conditions would the TH will yield the best results. There is also a need for proper long term follow up studies.

Future

There also needs to be extensive and maintainable improvements in all aspects of antenatal care and in the basic level of newborn resuscitation in low income countries. This will decrease the burden of disease and allow health workers to determine quickly which neonates require potential neuroprotection using TH. Although the development of TH for asphyxiated neonates has the possibility to prevent death and severe disability, its application is likely to raise numerous ethical challenges. There are definitely a few unanswered queries regarding the safety and effectiveness of cooling in low resource settings. There is a need to use caution in the adoption of TH in Indian neonatal units till further research is undertaken [39]. An interventional trial regarding TH for hypoxic babies using phase changing mattress and analyzing their MRI abnormalities at 5 d of life is also underway (CTRI/2013/05/003693). The results of HELIX trials may also throw more light on TH in the Indian context.

Conclusions

A joint assessment between experts in hypothermia, epidemiologists, health economists, clinicians in developing countries and funding bodies is required to ensure that TH, a safe and effective neuroprotective therapy demonstrated in developed countries does not become an unsafe and ineffective practice for the resource restricted countries. The burden of death and disability in developing countries demands that, as evidence based intervention strategies are implemented, a possibly low cost and effective therapy should be assessed urgently through adequately powered studies initially in some carefully chosen tertiary centers with minimum standards of perinatal care which will be meticulously monitored by data and safety monitoring committee personnel [41].