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ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 7-11

The effect of whole body cooling in asphyxiated neonates with resource limitation: Challenges and experience


1 Department of Pediatrics, Command Hospital, Pune, Maharashtra, India
2 Department of Pediatrics, Base Hospital, New Delhi, India
3 Department of Pediatrics, Command Hospital, Chandigarh, India
4 Department of Pediatrics, Command Hospital, Bengaluru, Karnataka, India

Date of Web Publication6-Feb-2018

Correspondence Address:
Dr. Rahul Sinha
Department of Pediatrics, Command Hospital, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_59_17

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  Abstract 


Background: Whole-body cooling is now recommended for the treatment neonates with hypoxic-ischemic encephalopathy (HIE) if started within 6 h of birth and continued for 72 h has shown to reduce the mortality and morbidity (1–4). The literature search also mentions the therapeutic beneficial effect of whole-body cooling in moderate-to-severe birth asphyxia. We publish the effect of whole-body cooling in asphyxiated neonates with resource limitation. Materials and Methods: It was a prospective interventional study of newborns admitted for HIE from October 2014 to April 2016 in Neonatal Intensive Care Unit (NICU) of Military Hospital (Level 2). There were 1565 deliveries during this period and 65 neonates with perinatal asphyxia were admitted in the unit. They were divided into two group by computer generated number so that the selection bias was minimised. The inclusion and exclusion criteria were determined as per the predesigned proforma. According to inclusion criteria, thirty inborn cases were eligible for the study group. The other control group included thirty neonates who did not receive whole-body cooling and was given treatment as per standard protocol. The remaining five babies were not included in the study group as they had mild birth asphyxia. The ethical approval and written informed consent were taken before the intervention. Inclusion criteria - Neonates born beyond 36 weeks of gestation and weight more than 2000 Grams were included in the study. The other inclusion criteria were umbilical cord or a postnatal (in the 1st h of life) arterial blood gas pH of <7.0 or base deficit of more than or equal to 16 along with any two of the following: (1) Apgar score of <5 at 5 min; (2) positive pressure ventilation (PPV) initiated at birth and continued for at least 10 min; (3) risk factor (anyone) - intrapartum fetal distress, cord prolapse, placental abruption, and uterine rupture/dehiscence. Exclusion criteria - Neonates born before 36 weeks and reported after 6 h of birth were excluded from the study. Statistical Analysis: Statistical analysis was carried out by SPSS 17. The difference between the two groups was studied either by the nonparametric Mann–Whitney test for quantitative variables or by Chi-square test or Fisher's test for qualitative variables. Statistical difference was considered significant if P < 0.05. Results: The primary outcome was measured in terms of neurological examination at 18 months of age and secondary outcome was measured in terms of adverse outcome and complications. The detail clinical examination and Denver Development Screening test were used for the neurological and developmental assessment. The neurological outcome at discharge and at 18 months of age was better in neonates given whole-body cooling than in the control group. The normal neurological outcome at 18 months of age was 70% compared to control group of 43% with P= 0.02. Furthermore, the cognitive delay at 18 months of age was lesser than control group.

Keywords: Asphyxia, cooling, hypothermia, neurological


How to cite this article:
Sinha R, Venkatnarayan K, Negi V, Sodhi K, John B M. The effect of whole body cooling in asphyxiated neonates with resource limitation: Challenges and experience. J Clin Neonatol 2018;7:7-11

How to cite this URL:
Sinha R, Venkatnarayan K, Negi V, Sodhi K, John B M. The effect of whole body cooling in asphyxiated neonates with resource limitation: Challenges and experience. J Clin Neonatol [serial online] 2018 [cited 2018 Oct 17];7:7-11. Available from: http://www.jcnonweb.com/text.asp?2018/7/1/7/224810




  Introduction Top


Hypoxic-ischemic encephalopathy [HIE] remains a devastating complication in term newborn infants occurring in about 1–6 babies per 1000 live births.[1] The risk of death or severe disability in survivors of moderate-to-severe HIE is about 60%. Even infants without motor impairments may have cognitive deficits, poor scholastic achievement and often require special educational needs.[2],[3] Asphyxia is the impairment of placental gas exchange leading to hypoxemia, hypercapnia, and metabolic acidosis in the fetus. The hypoxic-ischemic insult results in encephalopathy and other organ dysfunction (especially liver, renal, etc.). Following hypoxic-ischemic insult, some neuronal death take place which is primary cell death, and after latent period, secondary energy failure takes place which result in delayed neuronal death lasting for many days.[4] Therapeutic hypothermia (TH) is now recommended for the treatment neonates with HIE if started within 6 h of birth and continued for 72 h has shown to reduce the mortality and morbidity.[5]


  Materials and Methods Top


It was a prospective interventional study of newborns admitted for HIE from October 2014 to April 2016 in Neonatal Intensive Care Unit (NICU) of Military Hospital (Level 2). There were 1565 deliveries during this period and 65 neonates with perinatal asphyxia were admitted in the unit. They were divided into two groups by computer-generated number so that selection bias can be minimized. The inclusion and exclusion criteria were determined as per the predesigned pro forma. According to inclusion criteria, 30 inborn cases were eligible for the study group. The other control group included thirty neonates who did not receive whole-body cooling and was given treatment as per standard protocol. The remaining five babies were not included in the study group as they had mild birth asphyxia. The ethical approval and written informed consent were taken before the intervention.

Inclusion criteria

Neonates born beyond 36 weeks of gestation and weight more than 2000 g were included in the study. The other inclusion criteria were umbilical cord or a postnatal (in the 1st h of life) arterial blood gas pH of <7.0 or base deficit of more than or equal to 16 along with any two of the following: (1) Apgar score of <5 at 5 min; (2). positive pressure ventilation (PPV) initiated at birth and continued for at least 10 min; (3) risk factor (anyone) - intrapartum fetal distress, cord prolapse, placental abruption, and uterine rupture/dehiscence.

Exclusion criteria

Neonates born before 36 weeks and reported after 6 h of birth were excluded from the study.

Statistical analysis

Statistical analysis was carried out by SPSS 17 (IBM, Bangalore, India). The difference between the two groups was studied either by the nonparametric Mann–Whitney test for quantitative variables and by Chi-square test or Fisher's test for qualitative variables. Statistical difference was considered significant if P < 0.05.

Interventions

The neonates were cooled to 33.5°C ± 0.5°C for 72 h using ice packs wrapped in sterile towel in an open care system with warmer switched off. The rectal temperature was measured with rectal probe of multifunctional monitor. The time taken to achieve the target temperature was around 50 ± 5 min. The average time to start cooling was 3.2 ± 1.2 h. The target temperature was maintained without much problem. The mean average temperature difference between rectal and skin was 0.15°C ± 0.10°C. The vital parameters were monitored very closely. After 72 h of hypothermia, the newborn was gradually warmed from 0.2°C to 0.4°C/h (6–12 h). It took almost 12 h to bring the temperature to 36.4°C. The variation in the mean rectal temperature from the target temperature during the period of cooling was 0.09°C ± 0.04°C. The data were collected from clinical case sheet and various parameters such as gestational age, birth weight, sex, mode of delivery, acute intrapartum events, Apgar score at 1, 5, and 10 min, the need of neonatal resuscitation, and severity of HIE as assessed before cooling (Sarnat and Sarnat criteria) [Table 1] and [Table 2] were recorded. All treatment including medications (antibiotics, anticonvulsants, inotropes, and sedatives), ventilation, and use of blood products were as per standard treatment protocols. After repeated neurological examination in first 6 h, it was again done at 24 and 48 h. Serum electrolytes, blood urea, serum creatinine, prothrombin time, activated partial thromboplastin time, liver enzymes, and blood counts were monitored at 0, 24, 48, and 72 h and sepsis profile if required. Blood gas was done at 0, 2, 8, 12, 24, 48, and 72 h. An electrocardiogram was obtained if the heart rate was <80/min). For infants in the study group, we have registered the time of cooling, initiation after birth, the rectal temperature monitoring, the adverse effects, and the interventions during cooling.
Table 1: Maternal features

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Table 2: Neonatal features

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  Results Top


The primary outcome was measured in terms of neurological examination at 18 months of age and secondary outcome was measured in terms of adverse outcome and complications [Table 3], [Table 4], [Table 5]. The detail clinical examination and Denver Development Screening test were used for the neurological and developmental assessment. The neurological outcome at discharge and at 18 months of age was better in neonates given whole-body cooling than in the control group. The normal neurological outcome at 18 months of age was 70% compared to control group of 43% with P= 0.02. Furthermore, the cognitive delay at 18 months of age was lesser than control group.
Table 3: Adverse event during cooling

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Table 4: Course during Neonatal Intensive Care Unit stay

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Table 5: Neurological outcome at 18 months of age

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  Discussion Top


In this study, we present our data with whole-body cooling in asphyxiated neonates with the use of ice packs wrapped in sterile towel due to resource limitation, but the results are comparable to the studies, in which expensive machine was used for cooling.[6],[7],[8] Our results are encouraging with respect to the feasibility and safety of whole-body cooling and the beneficial effect in terms of survival and neurodevelopmental outcome. Two principal methods of cooling exist selective head cooling and the total body cooling. No superiority of either modality is supported by the existing evidence.[9],[10] However, the selective cooling is associated with a large gradient of intracerebral temperatures. The temperature difference measured at 2 cm depth of the cortical surface is typically 1.3°C ± 1.1°C; it reached 7.5°C ± 3.5°C during the selective cooling. The distribution of the intracerebral temperature is more homogeneous in the case of total body cooling (cortical area and deep brain gradient is 1.5°C ± 1.2°C at baseline and 1.1°C ± 0.9°C during the body cooling).[11],[12] In this study, we used the whole-body cooling for hypothermia. The best time to start cooling in asphyxiated neonates is before 6 h so that secondary neuronal injury can be prevented. In fact, Thoresen and Whitelaw suggested to start cooling babies before 3 h of age to obtain the optimal neuroprotective effect,[11] and in the TOBY study, hypothermia was more effective in children treated during the first 4 h after birth.[12] The average time for starting cooling was 3.2 ± 1.2 h in this study. The vital parameters along with repeated neurological examination and laboratory investigation have been carried out to stage the hypoxic ischemic encephalopathy to start whole-body cooling for maximum benefit. The core temperature is recorded by esophageal or rectal probe. The axillary temperature measurements have been reported to give variable data and therefore should not be preferred over core temperature measurement methods.[13],[14] The continuous monitoring of core temperature in this study was from a rectal probe. The maternal antepartum hemorrhage and fetal bradycardia were statistically significant for the outcome [Table 1]. Furthermore, cord blood PH and base deficit were statistically significant [Table 2]. In study group, the renal and hepatic injury was lesser than in control group which is in agreement with the study of Róka et al.,[15] who suggested a beneficial effect of hypothermia in other organs such as the kidney and liver by reducing the cell lysis secondary to the anoxic-ischemic attack, this renal protective effect was even found in the work published by Delnard et al.[16] where they noted a significant decrease in transient renal failure rates in treated children. The NICU stay in the study group was almost similar to control which was also found in the randomized study of Shankaran et al.[6] Furthermore, the start of enteral feed was slightly early in study group compared to control group by ± 1 day. The longer NICU stay was attributable to sepsis, especially in low- and middle-income country; however, our study is contradicting the literature data as there was only three (10%) case in the study group.[17] The subcutaneous fat necrosis generally developed after 10 days of life involving face/trunk and neck. It subsided by 1 week on its own and there was no hypercalcemia documented. The normal neurological outcome at 18 months of age in study group was 70% compared to 43% in control group with P= 0.02. Furthermore, the cognitive delay was less in study group (16% vs. 40% with P= 0.03) [Table 5]. The incidence of epilepsy and hearing loss was almost similar in two groups. The challenges were in the identification of newborns with moderate-to-severe HIE which may be mildly affected initially and may progress to a worse stage overtime, but the critical therapeutic window may be missed. Repetitive neurological examination, blood gases, and some other biomarkers may help make the diagnosis on time. Once TH is started, core temperature monitorization together with other vital signs is required. Particular attention should be paid to maintain normocarbia, normoxia, normal blood glucose levels, and normal BP. Electrolytes, liver-renal function tests, complete blood count, and coagulation tests need to be followed at least daily, and abnormalities should be treated accordingly. Thrombocytopenia is another expected finding during hypothermia together with impaired thrombocyte functions and may require supplementation. Fluid and TPN administration should depend on fluid balance. Nutrition should be started and increased slowly due to the risk of ischemic bowel disease. Antibiotic administration is required due to increased risk of infection. Seizures should be detected and treated appropriately. Drugs administered for infection, sedation, or seizure control may have delayed clearance during hypothermia. The limitation of the study was less number of neonates in the study group, Amplitude-integrated electroencephalogram was not available in our set up and improvised cooling technique was used for the hypothermia. A larger randomized controlled trial is required especially with resource limitation to validate the above study.


  Conclusion Top


Our research clearly shows that even with resource limitation of using whole-body cooling, the outcome of asphyxiated neonate can be improved. However, larger randomized controlled trial is needed to validate the same. There is an urgent need to conduct trials looking at the efficacy and safety of cooling in resource limitation setting.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: Synthesis and meta-analysis of trial data. BMJ 2010;340:c363.  Back to cited text no. 9
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Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: Starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology 2013;104:228-33.  Back to cited text no. 13
    
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Landry MA, Doyle LW, Lee K, Jacobs SE. Axillary temperature measurement during hypothermia treatment for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2013;98:F54-8.  Back to cited text no. 14
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Róka A, Vásárhelyi B, Bodrogi E, Machay T, Szabó M. Changes in laboratory parameters indicating cell necrosis and organ dysfunction in asphyxiated neonates on moderate systemic hypothermia. Acta Paediatr 2007;96:1118-21.  Back to cited text no. 15
    
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Delnard N, Cneude F, Hamelin S, Emeriaud G, Berne-Audéoud F, Andrini P, et al. Assessment of a hypothermia protocol implementation for hypoxic-ischemic encephalopathy in term newborns. Arch Pediatr 2010;17:1425-32.  Back to cited text no. 16
    
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    Tables

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



 

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