European Journal of Cardiovascular Medicine

Asphyxia is a major problem worldwide, as it affects 3-5 neonates per 1000 live births, with subsequent moderate or severe Hypoxic ischemic encephalopathy (HIE) in 0.5-1 per 1000 live births1. Neonatal hypoxic ischemic encephalopathy has been associated with high risk of mortality and morbidity2. Around 10 % of affected infants die and 25% among survivors develop long term neurodevelopmental sequelae such as cerebral palsy, epilepsy and sensory and motor deficits1.Therapeutic hypothermia has been studied in several randomized control trials from high income countries and there is convincing evidence that Therapeutic hypothermia is a standard therapy for moderate to severe HIE to reduce neurological damage1. Therapeutic hypothermia can be instituted by selectively cooling the head or the whole body. Various methods are available for whole body cooling like ice and frozen gel packs, cooling fans, water bottles, phase changing material and servo control method. For selective head cooling ice around head and circulating water head caps are available3. We have used phase changing material as a cooling device in our study. It is easy to induce hypothermia, maintain target temperature and rewarm infants in slow and controlled manner without need for frequent changes and minimum risk of skin injury.

The evidence of neuroprotectant effect of therapeutic hypothermia in HIE is lacking in low- and middle-income countries due to limited staffing with limited training and unavailability of cooling devices.

India carries a large burden of neonatal deaths worldwide, and perinatal asphyxia and HIE account for a quarter of these deaths and an unknown number of survivors with lifelong disability4. So, this study is conducted to evaluate the neuroprotective effect of therapeutic hypothermia in infants with moderate to severe HIE in neonatal intensive care unit in India using phase changing material as a low-cost equipment.

This retrospective cohort study was conducted in the neonatal intensive care unit (NICU) of a tertiary care center in northern India. Twenty-one infants, aged up to two years, who received therapeutic hypothermia during their neonatal period were included in the study..

Inclusion criteria5 for therapeutic hypothermia-

1.      Post menstrual age (PMA) ≥ 35 weeks, Birth weight ≥ 2,000 gm.

2.      Age at presentation within 6 hours of birth

3.      Evidence of birth asphyxia as evidenced by any of the following-

a.      Apgar score at 5 min ≤ 5

b.      Need of IPPV till 5 minutes of birth

c.      Cord arterial blood obtained within 1 hour of birth, PH <7.0, base deficit ≥ 16.0

4.      Evidence of moderate to severe encephalopathy as       evidenced by any of the following-

a.      Clinical seizures

b.      Altered state of consciousness (lethargy, stupor, coma) and any of the following-

-          Hypotonia

-          Abnormal reflexes

-          Absent or weak suck

Exclusion criteria-

1.      Presence of lethal chromosomal abnormality (trisomy 13 or 18)

2.      Presence of severe congenital anomalies (complex cyanotic CHD, major CNS anomaly)

3.      Symptomatic systemic congenital viral or bacterial infection

4.      Significant bleeding diathesis

5.      Major intracranial bleed.

 Neonates assigned for therapeutic hypothermia were placed on a phase-changing material (PCM)-based cooling device (Miracradle). The target core temperature was maintained at 33.5 ± 0.5°C for 72 hours, followed by controlled rewarming at 0.2-0.5°C per hour until the temperature reached 36.5°C.

Rectal temperature was continuously monitored in all neonates and recorded every 15 minutes for the initial 4 hours, thereafter hourly. Oxygen saturation, heart rate, blood pressure, and respiratory rate were also continuously monitored. Urine output was monitored every 6 hours.

Neurological examination was conducted at admission and repeated daily until the fourth day of life. Glucose, blood gas, renal function, liver function, coagulation profile, full blood counts, and blood culture were also monitored.

Data collection

Retrospectively, medical data of infants who received therapeutic hypothermia were retrieved from medical records. An interview was conducted with the parents of the infants. The ASQ (age and stage questionnaire) method was utilized to assess the child’s development in all domains. The child was assigned a score, based on which the child’s development was categorized into three groups:

1.      Above the cutoff, indicating that the child’s development appears to be on track.

2.      Close to the cutoff, requiring the provision of learning activities and ongoing monitoring.

3.      Below the cutoff, necessitating further assessment with a professional..

Outcome-

Short term outcome was survival or non-survival at the end of hospital stay. Long term outcome was normal or abnormal development of the child at the age of 2 year. 

Statistical method-

The results were expressed as number and percentage.   

A total of 21 subjects were included in the study. Ninety percent of the study subjects were male, while ten percent were female. The majority of the patients (76%) were delivered via vaginal delivery, while the remaining 24% were delivered via laparoscopic single-incision surgery..

Of the 62 study subjects, 62% required bag and mask ventilation for resuscitation, while the remaining 38% required intubation. All patients necessitated respiratory support. The majority (67%) required high-flow nasal cannula (HHFNC) support, while 19% were ventilated. The remaining patients required nasal prongs only. Seizures were observed in 90% of patients during their hospital stay. Culture results were positive in 19% of patients. 28% of patients exhibited indirect signs of sepsis. Respiratory distress syndrome (RDS) was the most prevalent respiratory complication (28%). Pneumothorax was noted in one patient, necessitating the insertion of an internal drainage tube. 24% of patients required ionotropic support due to shock. All infants developed hypoxic ischemic encephalopathy (HIE). Of these, 18 (85%) were classified as HIE II, while 3 (15%) were classified as HIE III. 81% of patients survived. Long-term follow-up revealed that 70% of patients exhibited normal development (Table 1).

Table 1: Baseline characteristics of study subjects

The study subjects exhibiting delay are further categorized into two distinct groups. One infant exhibited delay that was situated near the threshold range, while the remaining four infants fell below the cutoff range. The most frequently affected domain was “problem-solving,” which was observed in 80% of the study subjects. Conversely, the least commonly affected domain was “gross motor.” (Table 2).

Table 2: ASQ scoring of cases with developmental delay

Major randomized controlled trials have shown a beneficial effect of therapeutic hypothermia on survival and long-term neurological outcomes for newborns who suffered from HIE using either selective hypothermia5 or whole body cooling6. But the data from low- and middle-income countries are lacking. So, the present study presented the experience with therapeutic hypothermia by whole body cooling using phase changing material (PCM) in asphyxiated neonate with moderate to severe HIE in a low-income country.

The main aim of therapeutic hypothermia is to reduce metabolic rate and oxygen consumption to preserve cerebral integrity and improve survival and neurological outcome. Hypothermia results in graded reduction in cerebral metabolism, suppresses apoptotic processes and also suppresses release of pro-inflammatory cytokines and interleukins. Three systemic reviews concluded that therapeutic hypothermia can significantly reduce death and neurodevelopmental disability after neonatal encephalopathy and that is safe in an intensive care setting. Various cost-effective methods available for whole body cooling like ice and frozen gel packs, cooling fans, water bottle and phase changing material5,6.

Various trials have been done to know the methods and efficacy of hypothermia like ‘Cool cap trial’ which used selective head cooling with mild systemic hypothermia, ‘NICHD trial’ of whole-body cooling, and ‘TOBY trial’ of whole-body cooling. All trials have considered therapeutic hypothermia to be effective in reducing neurological damage in infant with HIE.1

In our study 21 asphyxiated neonates were included, all of them were fulfilling the inclusion criteria. Out of these asphyxiated newborns 19 (90%) were males and 2 (10%) were females and Gestation wise all were term newborns, mean gestation age was 39 weeks. All cases of asphyxia were having HIE (II-III). 21 asphyxiated neonates were studied, all of them were fulfilling the inclusion criteria. Out of these asphyxiated newborns 19 (90%) were males and 2 (10%) were females and Gestation wise all were term newborns, mean gestation age was 39 week. In a study done by Dag et al7. 20 (55%) were males and 16 (44%) were females and 32 (88.8%) were term newborns and 4 (11.11%) were preterms. In our study all cases of asphyxia were having HIE (II-III). Dalal et al study showed 32.5% cases of asphyxia were having HIE8. 

Two types of PCM block were used FS-29 with melting point of 29ºc and FS-21 with melting point of 21ºc. Thomas et al9 also used PCM blocks with different melting points

(29ºc and 21ºc) similar to those of our study. The use of PCM mattresses with multiple melting points facilitated precise cooling in infants with differing levels of heat production. Many other low tech cooling methods, such as ice or frozen gel packs are available but they may results in marked temperature fluctuations and shivering, with potential loss of neuroprotective efficacy10.

The use of PCM mattresses with multiple melting points facilitated precise cooling in infants with differing levels of heat production. In our study 81 % patients were survived and 70 % infants are having normal development at 2 year of age. Only 5 infants showed developmental delay at 2 year of age which was assessed using ASQ score.

Tran et al11 conducted a study on 52 infants using phase changing material as a cooling device similar to our study in low resource settings and found that cooling with PCM device was comparable to the standard servo-controlled system in maintaining the target temperature and considered it to be an effective and cost beneficial method. 

Shabeer MP et al12 conducted a comparative study in 68 newborns using two low cost methods of cooling, 23 babies using frozen gel packs (FGP) and 45 babies using phase changing material (PCM) and found that both PCM and FGP are effective and safe, comparable with standard servo-controlled cooling equipment. PCM has the advantage of better maintenance of target temperature with less nursing input, when compared with FGP.

Similarly, Saraswat D13 et al conducted a study on 50 neonates who have received therapeutic hypothermia using phase changing material, and on follow up at 12 months found that 36 babies had normal neurological examination, only 3 had psychomotor delay and 1 baby needed long term anticonvulsant. 10 neonates died during the stay and conclude PCM to be a cost-effective method which can reduce the progression of hypoxic damage.

In summary, our study is among the few conducted in India that concluded that infants with HIE can be effectively cooled using phase-changing material. Furthermore, this approach offers neuroprotective efficacy in a cost-effective manner.

LIMITATIONS OF THE STUDY

1.      The study requires trained nurses and pre-specified interventions, such as inserting a cloth sheet between the infant and PCM blocks, covering the infant, or switching on the radiant warmer to maintain the target temperature.

2.      Amplitude EEG studies are not performed prior to initiating therapeutic hypothermia.

The utilization of PCM mattresses presents an effective and economical approach to cooling infants in low- and middle-income countries. It facilitates the induction of hypothermia, the maintenance of the desired temperature, and the gradual rewarming of infants without the necessity for frequent alterations and minimizing the risk of skin damage. Nevertheless, it is imperative to ensure meticulous monitoring and provide exemplary nursing care.

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