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Use of Hypothermia in the Asphyxiated Infant
Ela Chakkarapani MRCPCH and Marianne Thoresen MD, PhD.
 Perinatology 2010; 3:20-29
 

Clinical Case

A 32 year old primiparous woman presented with decreased fetal movements and her cardiotocograph (CTG) showed sinusoidal trace. She was taken up for emergency Cesarean section. A 39 weeks female baby was delivered. She was pale; there was no spontaneous breathing and the heart rate was less than 100/min. She was dried and wrapped, intubated and CPR was commenced. Venous cord pH was 6.9, base deficit 23 mmol/L and pCO2 72 mmHg; arterial cord pH was 7.01, base deficit 16 mmol/L and pCO2 50mmHg.

  
Dr Ela Chakkarapani is a Research Fellow and Dr. Marianne Thoresen is Professor of Neonatal Neuroscience Department at .
St Michaels Hospital, CSSB, Department of Child Health ,University of Bristol, UK.
E-mail: marianne.thoresen@bristol.ac.uk
 

Introduction

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 (liver, renal etc.) Some brain cells die during the hypoxic-ischemic insult (primary cell death). Following the latent phase whose duration depends on the severity of the hypoxic-ischemic insult [4], secondary energy failure with delayed neuronal death occurs which can last for several days [5]. During the latent phase, there is an apparent normalisation of cerebral metabolism followed by initiation of cytotoxic mechanisms, activation of necrosis and apoptosis pathways, release of excess neurotransmitters leading to excitotoxicity during the secondary energy failure [5] .
 

Hypothermia

Experimental studies & mechanism

Many years of experimental work support the use of hypothermia after hypoxic-ischemic insult [6]. Animal studies have shown a reduction in cerebral injury and improvement in neurological function, when the core temperature is reduced by 3-5°C after the hypoxic-ischemic insult [7-9]. The precise neuroprotective mechanism of hypothermia is not fully described; however hypothermia suppresses many of the pathways leading to delayed cell death. Hypothermia reduces cellular metabolic demands [10], reduces excessive accumulation of cytotoxins such as glutamate, nitric oxide and oxygen free radicals [11], and suppresses necrosis and apoptosis [12, 13]


 Clinical Trials

Three published multicentre randomised controlled trials of hypothermia in newborn infants with HIE and two trials  which presented only the results [14, 15] have shown improved outcome in the cooled group. The CoolCap trial used selective head cooling with mild systemic hypothermia (rectal temperature 34-35°C) commenced within 5.5 h of age for 72 h; and showed an independent protective effect of hypothermia on the primary outcome of death or disability at 18 months (odds ratio 0.52, 95% CI 0.28–0.70, p=0.04) in the full study population (n=218), when modified Sarnat score, Apgar scores, aEEG background and seizures were used in logistic regression [16, 17] The NICHD trial of whole body cooling (oesophageal temperature 33.5°C for 72h) showed a significant reduction in the risk of death and moderate to severe disability at 18 months in the hypothermia group [18]. The TOBY trial of whole body cooling (rectal temperature 33.5°C for 72h) did not show a significant effect on the same primary outcome, however there was significant improvement in neurologic outcome in survivors from the hypothermic group [19]. The preliminary results of additional primary trials from Shanghai, China (Wen-hao Zhou and colleagues), neo.nEuro.network study [15] and ICE trial [14] further support a beneficial effect of hypothermia. Systematic review of the three trials showed a significant reduction of combined rate of death and severe disability with a number needed to treat of 9 (95% CI 5 to 25) and increased normal survival (survival without cerebral palsy and with MDI and PDI>84 and normal vision and hearing) with a NNT of 8 (95% CI 5 to 7) [20]. The eligibility criteria used in the clinical trials are given in Table 1.


Current situation

Many countries and individual hospitals have introduced cooling as standard of care for term infants who fulfill the trial entry criteria for therapeutic cooling but others are awaiting guidelines from International Liaison committee on Resuscitation ILCOR (http://www.ilcor.org/en/home/). National Institute for health and Clinical Excellence (NICE) in the UK recommended recently that cooling after perinatal asphyxia should be supported (http://guidance.nice.org.uk/IPG347/Guidance/pdf/English) .
 

Table 1. Eligibility Criteria for Therapeutic Hypothermia

Entry criteria

≥ 36 weeks' gestation

CoolCap &TOBY trial

NICHD trial

Metabolic    A

pH < 7 OR

Base deficit ≥ 16 mmol/L in the first hour  OR

Apgar  < 5 @ 10 min OR

10 min continued resuscitation

pH < 7 OR

Base deficit ≥ 16 mmol/L in the first hour

If blood gas unavailable,  pH 7.01-7.15, or base deficit between 10 and 15.9 then

Acute perinatal event AND

Apgar < 5 @ 10 min OR

> 10 min assisted ventilation

Neurology   B 

Lethargy, stupor, or coma

AND

One or more of below

  • Hypotonia

  • Abnormal reflexes :
    oculomotor / pupillary

  • Suck: weak / absent

  • Clinical seizures

One or more signs in at least 3 categories

  •  Consciousness: Lethargy, stupor or coma

  • Tone: Hypotonia, flaccid

  • Autonomic : Pupils – constricted / dilated / unreactive;

  • Heart rate – Bradycardia / variable ;       

  • Respiration- periodic breathing / apnea

  • Primitive reflex: suck : weak / absent

  • Moro: incomplete / absent

  • Spontaneous activity : decreased / nil activity

  • Posture: distal flexion / complete extension.

  • Clinical seizures
 aEEG          C

Abnormal aEEG

No aEEG


Abnormal amplitude integrated EEG [21] can be of moderately to severely abnormal category in the voltage classification system [22]; or discontinuous normal voltage to flat trace in the pattern classification system [21, 23].  
 

Figure 1. Classifications of 5 example traces by using the pattern recognition method (right)  and voltage method (left) to assess the aEEG background at 3 to 6 hours of age.  (Click image to enlarge)

 From Thoresen M, et al. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics. 2010 Jul;126(1):e131-9. PMID:9563847 Reprinted with permission of  The American Academy of Pediatrics

 

Clinicians who do not have access to the technology or the expertise of aEEG can use the clinical criteria as enlisted in the NICHD criteria in the table above. It is highly recommended to adhere to the eligibility criteria of the trials while considering asphyxiated term infants for cooling with regards to the gestation, duration, depth and the therapeutic window, and cooling infants outside these criteria will be experimental.

Management of Asphyxiated Infants in the Delivery Suite

 If severe clinical asphyxia is apparent, the overhead heater should be turned off as soon as effective ventilation and heart rate is achieved. Active heating in the transport incubator and wearing hats are actively discouraged. Rectal (6cm from the anal verge) or oesophageal temperature monitoring should be commenced within 20 minutes of birth [24].  Active cooling is rarely needed as the reduced heat production and impaired metabolism will reduce the core temperature.
 

Cooling devices

There are several servo-controlled cooling devices which can be used to cool and maintain core temperature at the target of 33.5°C during transport. The following table from the review about techniques of cooling devices [25] lists the available devices. A recent comparison of Tecotherm TS med 200,MTRE criticool and CoolCap showed that these devices respectively maintained target temperature  for 81%, 97% and 76% of the duration of cooling. There was no difference in mean BP or HR during cooling between the the three methods. There was greater variation in rectal temperature during rewarming in selective head cooling compared to whole body cooling [26].
 

Table 2. High-Tech Cooling Devices   (Click image to enlarge)

Table 3.   Low-Tech Cooling Devices      (Click image to enlarge)

Tables 2 and 3 reprinted from Semin Fetal Neonatal Med doi:10.1016/j.siny.2010.03.006 .Robertson NJ , et al. Techniques for therapeutic hypothermia during transport and in hospital for perinatal asphyxial encephalopathy Copyright (2010) with permission from Elsevier
 

Initiation of Therapeutic Hypothermia

Initiation of therapeutic hypothermia comprise of induction, maintenance and rewarming phases. Experimental studies indicate that the earlier the cooling is commenced the better the outcome [27]. The natural reduction in core temperature after asphyxia and avoiding active warming has reduced the induction phase in most situations. A systematic neurological assessment as in Table 1 with aEEG assessment is needed to decide if the infant qualifies for therapeutic hypothermia. In the clinical trials, a minimum of 20 minutes of aEEG was recorded within the first 6 hours to decide eligibility. aEEG should be monitored for a longer duration preferably 6 hours before concluding the ineligibility for therapeutic hypothermia. If the infant does not qualify for hypothermia, slow rewarming can be commenced at a rate of 0.2°-0.4°C/h. There can be overshooting of the target temperature during induction of cooling in some cases. However, with the servo-controlled devices, overshoot does not occur [26].


 Maintenance Phase

The target core temperature of 33.5°C and 34.5°C is maintained for 72 hours with whole body cooling and selective head cooling respectively. The goal during the maintenance phase is to avoid large fluctuations in the core temperature, monitor and maintain physiology within the normal range. Though there is no data delineating the independent effect of the fluctuations of core temperature on the neurological outcome, it is possible that large temperature fluctuations can lead to unfavourable cardiovascular and cerebral hemodynamic fluctuations.


Re-warming Phase

In animal studies, fast re-warming may transiently affect the cerebral blood flow- metabolism balance and affect the neuronal cytoskeleton [28, 29]. During re-warming, seizures, hypotension [24], hypoglycaemia or hypokalemia can occur. Seizures usually respond to anticonvulsants; slowing down the pace of rewarming or halting the rewarming briefly is recommended [24]. During rewarming, the dilation of skin blood vessels and decreased effective blood volume can lead to hypotension if the intravascular compartment is not adequately filled. Though the clinical trials have re-warmed at a rate of 0.5°C/h, we suggest a slower rate of 0.2°C/h in the first two hours and 0.4°C/h thereafter to reach the normothermic target of 36.5°C [30]. We also recommend monitoring core temperature for a further 24 hours after attaining normothermia to avoid hyperthermia after rewarming, as hyperthermia (> 36.5°C) can affect the neurodevelopment outcome [30, 31].


Intensive Care During Hypothermia

Ventilation

Most of the asphyxiated infants present with mixed metabolic and respiratory acidosis. Most severely asphyxiated infants need respiratory support. We aim to maintain normocapnia, as fluctuations in pCO2 may worsen the cerebral blood flow perturbations in the asphyxiated infants. However, their own and compensatory respiratory drive often causes hypocapnia, despite mechanically ventilated. Though there is evidence for hypocapnia causing adverse neurodevelopmental outcome in preterm ventilated infants [32, 33], this has not been documented in the term infants and spontaneously breathing hypocapnic postasphyxic term infants can have good short term neurologic outcome [34]. Hypocapnia < 2.6 KPa (OR 2.34, 95% CI 1.02 to 5.37) and hyperoaxemia >26.6KPa (OR 3.85, 95% CI 1.67 to 8.88) individually increased the risk of adverse outcome in normothermic asphyxiated term newborn infants, and the combination of both hypocapnia and hyperoxaemia further increased the risk of adverse outcome (OR 4.56, 95% CI 1.4 to 14.9) [35]. The decreased metabolism associated with hypothermia will reduce the CO2 production [10] The incidence of Persistent Pulmonary Hypertension (PPHN) in the clinical trials is similar in the normothermic and hypothermic groups [16, 18, 19].  In asphyxiated infants with PPHN, we provide hypothermia along with the standard therapy for PPHN (i.e, high Fraction of inspired oxygen and inhaled nitric oxide). There is no difference in the occurrence of PPHN between selective head cooling or whole body cooling [36].

The partial pressure of CO2 is reduced by 4% per degree centigrade reduction in core temperature [37].  There is higher cerebral blood flow with higher PCO2 [38] and reduced threshold for seizures with hypocapnic alkalosis [39]. Hence, in ventilated infants cooled to 33.5°C, we shift the normal PCO2 range of 36-44mmHg at 37°C to 41-51mm Hg. We use the same normothermic range for pO2 and pH as the influence of temperature on these variables is less [24].


Cardiovascular function

Hypothermia decreases cardiac output and heart rate (sinus bradycardia). No large effect on stroke volume, blood pressure and cardiac performance has been reported during hypothermia [40, 41].  Hypothermia does not cause arrhythmia; in fact low temperature stabilizes  cardiac conduction and is a recommended treatment for junctional ectopic tachycardia [42]. Hypotension needs prompt correction as it may affect cerebral blood flow in the face of deranged cerebral autoregulation.

 
Central nervous system

Electrical and clinical Seizures should be actively monitored using aEEG and treated, as seizures worsen neurodevelopmental outcome independent of the severity of hypoxic-ischemic brain injury [43]. Though hypothermia has been reported to reduce the duration of seizures in experimental studies, [9, 44] there has been no substantial difference in the clinical trials  [16, 18, 19].   


Infection

The incidence of proven sepsis in the normothermic and hypothermic groups in the 3 trials vary between 2 and 12%. Infection is not an exclusion criterion for cooling as this diagnosis is rarely known at birth. There is no evidence that infection in asphyxiated newborns was worsened by hypothermia.

 
Glucose and Electrolytes

Glycemic control and electrolytes particularly magnesium should be maintained within the normal ranges. Hypo or hyperglycemia may affect neuroprotection. Magnesium can increase the threshold for shivering. There is experimental evidence for the neuroprotective effect of magnesium [45]. Postnatal magnesium sulphate infusion in asphyxiated newborn infants maintaining Mg ≥ 1.2mmol/L improved the short term outcome [46].  In adults, Mg > 1mmol/L have been shown to reduce shivering during HT. We suggest to keep plasma Mg~ 1mmol/L. However supranormal levels (> 2.5 mmol/L) can lead to unacceptable hypotension and respiratory depression [47 ].


Clotting/bleeding disorder

Asphyxiated neonates often have abnormal clotting. Ideally one would like to correct this first and then cool, however the therapeutic time window for cooling will be lost. Although it is a fact that hypothermia prolongs bleeding time, there was no difference between normothermic and hypothermic infants in the trials regarding the complication related to abnormal coagulation. Nonetheless, clinical increased bleeding tendency should be treated as soon as possible, before any clotting results are available to avoid treatment delay.  
 


Hypothermia in Low Resourced Settings

In low resourced settings, there are many ethical issues to be considered. It is argued that evidence for hypothermia comes from countries who can afford decent health care and extrapolating the evidence may not be appropriate. The patient population is very likely to differ with either more of severely asphyxiated infants or their early demise, can leave a population of moderately asphyxiated infants. Most of these infants are naturally hypothermic which may offer natural neuroprotection. Some argue that infants in low resource settings should be maintained normothermic and hypothermia is still experimental, which is ethically debatable. Though cooling can be achieved with many low cost techniques, there should be adequate counseling of parents of the long term outcome, where the burden of looking after infants with disabilities is unaffordable and one often visits the question of acting in the best interest of the infant and the risk benefit balance. The ongoing trials in the low resource settings must take this into account during the informed consenting process. There was a trend of increased poor outcome in the cooled group in the two pilot studies undertaken in Uganda [48] and India.  
 

Future of Neuroprotection in Asphyxiated Infants

NNT of 9 is a fantastic result for the three first ever large trials in newborns with perinatal asphyxia. It is likely that the effectiveness of hypothermia could be improved by improved protocols and intensive care. Many research groups study HT combined with other drugs. Inhaling the inert gas Xenon while hypothermic doubles the neuroprotection in both small [49] and large animal model [50]. Anticonvulsants [51, 52] and erythropoietin [53] have yielded neuroprotection in animal and human studies. However, there is a lack of data on combination of these with optimum duration of HT. Entering data locally as well as internationally like the Vermont Oxford Network is important to document outcome in the clinical setting. This part of the journey may be less exciting than the previous one but equally important. The outcome after specialist treatment improves with experience and patient volume in the treating institutions [21]. To develop and validate a new treatment and improve protocols rigorous documentation and follow up is needed. While it is advisable to centralise the management of medically very sick infants in cooling centres, it is equally important to educate all hospitals with obstetric and newborn care, the entry criteria for cooling therapy, diagnostic evaluation and the initiation of early cooling before transport team arrives.

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