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Year : 2016  |  Volume : 5  |  Issue : 1  |  Page : 8-17

Therapeutic hypothermia in neonatal intensive care unit: Challenges and practical points

Division of Newborn Medicine, Gazi University Hospital, Ankara, Turkey

Date of Web Publication6-Jan-2016

Correspondence Address:
Ebru Ergenekon
Division of Newborn Medicine, Gazi University Hospital, Beşevler, 06500 Ankara
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2249-4847.173271

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Therapeutic hypothermia (TH) is used for hypoxic ischemic encephalopathy (HIE) of the term or near-term newborns to reduce the possible neurological handicap. The aim of this review is to focus on monitorization and management of newborns undergoing TH in Neonatal Intensive Care Unit. MEDLINE search was performed with keywords “therapeutic hypothermia, newborn.” Articles on human subjects published between 2004 and 2015 were included. TH is defined as moderate hypothermia where the core body temperature measured by the esophageal or rectal probe is cooled down to 33.0–35°C for 72 h. It may be administered by selective head cooling or with total body cooling methods by using a variety of different devices. TH is suggested to be used within certain guidelines in newborns with moderate to severe HIE meeting definitive criteria. For best results treatment needs to be started no later than 6 h of life which at times may be challenging for the clinician in newborns who initially appear mildly affected but later on progress to have more severe disease. TH has been used in many multicentered clinical studies showing neuroprotective effects. However, it has several effects that the clinician needs to be aware during treatment including; cardiopulmonary, renal, hematological, and metabolic effects. Drug metabolism may be delayed, there may be clotting disorders and the tendency for infection and skin problems as well. Optimal patient care including adequate sedation, antibiotic treatment, fluid, and nutritional management are very important during the course of TH. Patients need to be fully monitored including vital signs particularly core temperature. Frequent blood work may be necessary to follow the general condition of the patient and side effects. Echocardiographic assessment, head ultrasound, amplitude integrated electroencephalography are other methods used to evaluate treatment effects and guide management. Rewarming after 72 h of TH is also a very important part of treatment. Rewarming should be completed within 4–12 h and close follow-up including vital signs, respiratory, and circulatory conditions is required to detect the changes occurring in the patient and treat accordingly.

Keywords: Hypothermia, hypoxic ischemic encephalopathy, newborn

How to cite this article:
Ergenekon E. Therapeutic hypothermia in neonatal intensive care unit: Challenges and practical points. J Clin Neonatol 2016;5:8-17

How to cite this URL:
Ergenekon E. Therapeutic hypothermia in neonatal intensive care unit: Challenges and practical points. J Clin Neonatol [serial online] 2016 [cited 2022 Aug 8];5:8-17. Available from: https://www.jcnonweb.com/text.asp?2016/5/1/8/173271

  Introduction Top

Therapeutic hypothermia (TH) is used for hypoxic ischemic encephalopathy (HIE) of the term or near-term newborns to reduce the possible neurological handicap. Although the current expert opinion is to apply TH only within a well-established protocol in experienced centers the actual practice is rapidly shifting away from this suggestion and TH is being applied in many Neonatal Intensive Care Units (NICUs) with poor resources and limited experience especially in developing countries.

The aim of this review is to focus on monitorization and management of newborns undergoing TH in NICU with particular emphasis on challenges during cooling and rewarming.

MEDLINE search was performed with keywords “therapeutic hypothermia, newborn,” filtering was applied so that only the articles on human subjects published between 2004 and 2015 were included. Case series and case reports, as well as reviews, were particularly included for they provided important information on the clinical experience of physicians using TH for HIE. Of the 758 articles in English language found on PubMed the ones related to single case reports only, magnetic resonance imaging (MRI) findings, amplitude-integrated electroencephalography (aEEG) findings with relation to long-term prognosis, long-term follow-up studies were excluded and the review was prepared based on the remaining 150 articles.

The following main topics are covered in this review:

  • Definition and methods of TH for HIE
  • Indications of TH and decision making in the gray zone cases
  • Respiratory management during TH
  • Circulatory management during TH
  • Fluid, electrolyte, and nutritional management during TH
  • Renal problems during TH
  • Hematological complications during TH
  • Infection control during TH
  • Stress and pain management during TH
  • Other issues: Subcutaneous fat necrosis (SCFN), drug metabolism
  • Clinical follow-up and monitorization methods during TH
  • Rewarming; how to make it go smoothly?

  Definition and Methods of Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy Top

TH is defined as moderate hypothermia where the core body temperature measured by esophageal or rectal probe is cooled down to 33.0–35°C for 72 h followed by slow rewarming (0.2–0.5°C/h). TH can be applied by two methods: (1) By whole body cooling system where core body temperature is cooled down to 33.0–34.0°C, and (2) by selective head cooling system where the core body temperature is cooled down to 34–35°C.

There are a number of high technological devices for whole body cooling in which the main idea is circulating cool fluid in a cooling mattress or blanket around the baby. The baby's core temperature is continuously monitored during the procedure and in most of the devices the temperature of the fluid in the cooling system is servo controlled based on the desired core temperature of the baby. On the other hand currently there is one commercially available device for selective head cooling in which the fluid is circulated inside the cap that is wrapped around the head of the baby. The baby's core temperature is monitored continuously, and the core temperature is desired to be between 34°C and 35°C, which is maintained manually by changing the cap temperature or the environmental temperature.[1]

Apart from the high-tech devices there are other methods to apply TH in low resource settings. Gel or ice packs around head of the baby, cooling fans providing air circulation around the baby, phase changing materials placed around the body of the baby are some of the methods that are being used successfully where high technology is not available.[2],[3],[4] These methods have proven to be efficient in a small number of studies and may be considered in low resource settings provided core temperature is continuously monitored and acted upon if the temperature goes out of the desired range. The axillary temperature may have wide variations and gradient from core temperature, therefore, is not recommended as main temperature monitoring method during TH.[5]

  Indications of Therapeutic Hypothermia and Decision Making: Gray Zone Top

TH is suggested to be applied under the strict protocol to avoid uncontrolled use and complications.[6] If it is to be administered current knowledge suggests that the sooner, the better and definitely before the first 6 h of life. In fact it is even suggested by Thoresen et al. to cool babies before 3 h of age to obtain the optimal neuroprotective effect.[7] Large multicenter clinical trials including NICHD, TOBY, CoolCap, and neo.nEURO.network have all used similar protocols with minor variations to administer TH to newborns with moderate to severe HIE with or without aEEG finding as one of the inclusion criteria.[8],[9],[10],[11] [Table 1] summarizes the inclusion criteria for TH in four large clinical trials.
Table 1: Entry criteria of four clinical trials on therapeutic hypothermia

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However, after TH has become almost routine treatment for moderate to severe HIE it has become a challenge to recognize the moderately affected newborns on time to be able to cool those patients before 6 h of age. Clinicians taking care of this group of patients know very well that moderate HIE may not be evident in the first few hours of life and may appear as mild (sarnat stage I) HIE. Even aEEG may appear as normal especially if the patient has been transferred from another center, and passive cooling has been applied during transport. If not cooled or passive cooling is stopped with the idea that the patient is out of the inclusion criteria these patients may progress to have seizures within hours now making them eligible for TH but at this point the therapeutic window will be over. Therefore, it is a real challenge to recognize the moderate HIE (sarnat stage II) patients if the clinical picture is not straight forward from early on. Close and repetitive clinical assessment (every 1–2 h during the first 6 h) is required for these patients to determine the stage of HIE and if the HIE stage progresses from stage I to stage II TH should be started immediately. Olsen et al. suggest the following neurological assessment repeated every hour in newborns with perinatal asphyxia and start TH if the patient develops any 3 out of 6 neurological findings shown in [Table 2].[12]
Table 2: Moderate to severe encephalopathy if three or more of the following is present

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Thompson score of 5 or more has also been suggested to be useful in predicting moderate to severe HIE thereby facilitating decision making for TH in early hours of life.[13] Thompson score is shown in [Table 3].[14] Some of the biochemistry measurements including lactate, lactate dehidrogenase (LDH) creatinine phosphokinase (CPK) and uric acid over certain cut-off levels (4.4 mmol/L, 738 IU/L, 1196 IU/L, and 6.2 mg/dl, respectively) have been found to be helpful to diagnose HIE ≥ stage II early on when assessed together.[15]
Table 3: Thompson score

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Despite all of these clinical or laboratory findings, some of the moderate HIE babies may be overlooked, and TH may be delayed missing the valuable 6 h period. Perinatal acidemia itself has been found to be associated with abnormal outcome in 20% of the otherwise mild HIE appearing newborns.[16] Profound postnatal acidosis (pH < 7.00) within 1st h after birth has also been found to be predictive of bad outcome and early indication for potential TH.[17]

Therefore close clinical monitorization and repetitive neurological exam are crucial even in newborns who appear to be affected mildly. An alternative approach could be to start cooling in the patients where the clinician remains in doubt about the staging of HIE and then discontinue TH if the patient appears to be completely normal or has mild HIE in the first 24 h however this area remains to be the gray zone of TH application.

  Respiratory Management during Therapeutic Hypothermia Top

Maintaining normal blood gas values is very important for newborns with HIE. Extreme oxygen or carbon dioxide levels are both detrimental to the already injured brain. Hypocarbia particularly <35 mmHg [18] and hyperoxia (>200 mmHg) have been shown to increase neuronal injury in asphyxiated newborns and should be avoided.[19] Unfortunately, both of these conditions may occur very easily. The hyperoxia may start even in the delivery room with the exaggerated reflex of the physician to resuscitate the asphyxiated baby by providing 100% oxygen and may continue during and after transport to the NICU. Hypocarbia may also occur as a result of hyperventilation during resuscitation and continue during transport. Physicians resuscitating newborns should be aware of the damage that may be caused by hyperoxia and hypocarbia in this vulnerable population.

Once in the NICU and during TH the same cautions should be in practice. If the baby is on the ventilator, the support should be kept minimum to obtain optimal PaO2 and PaCO2 levels in arterial blood gases. Limited studies investigating the effects of whole body hypothermia on lung mechanics have shown that tidal volume and compliance increase during cooling and decrease after rewarming, and the authors caution clinicians about the necessity of close follow-up of respiratory functions during TH.[20] On the other hand at temperatures below 32°C hypothermia has been shown to cause transient chest stiffness necessitating increase in tidal volumes.[21]

Carbondioxide management: Maintaining normocarbia

It must be remembered that TH results in increased solubility of CO2 in the blood. The blood gas machines most of the time warm the blood up to 37°C for the measurement therefore the PaCO2 levels appear to be 2 mmHg higher than the real PaCO2 in blood gases for each degree of cooling.[22],[23],[24] In patients undergoing TH Thoresen et al., suggest to aim for PaCO2 levels of 41–51 mmHg to avoid hypocarbia and cerebral vasoconstriction.[24] However, this may not be easy to achieve particularly if the baby is not on a ventilator and breathing on its own. Causes of tachypnea such as pain and stress should be avoided. Rarely these babies may need to be heavily sedated and intubated to avoid hyperventilation and hypocarbia. Hypercarbia, on the other hand, is more easily managed if the baby is on the ventilator. PaCO2 levels over 55 mmHg should be avoided to prevent excessive cerebral vasodilatation and over perfusion. The baby may need ventilatory support to achieve this.

Oxygen management

TH increases the solubility of oxygen as well, therefore PaO2 measured by blood gas machines which increase the sample temperature to 37°C before measurement is approximately 5 mmHg higher than the actual PaO2 in the patient for each degree of hypothermia.[25] It should also be kept in mind that since hypothermia causes a leftward shift in the hemoglobin-oxygen dissociation curve the oxygen delivery to tissues will be decreased during treatment, however since oxygen consumption is also decreased due to decreased metabolic rate this is not considered to be a problem. In fact, as mentioned above hyperoxia is detrimental for the injured brain and minimum FiO2 to maintain normoxia is recommended in babies with HIE. Increased FiO2 has been shown to be associated with worse outcome in newborns undergoing whole body hypothermia.[26] However, it is also known that TH may cause increased pulmonary vascular resistance resulting in persistent pulmonary hypertension of newborn which in extreme cases may necessitate inhaled nitric oxide, other pulmonary vasodilator medications, extracorporeal membrane oxygenation,[27] or ending the treatment. Therefore oxygen saturation levels and PaO2 should be monitored closely to avoid both hypoxia or hyperoxia. Normal PaO2 levels of 50–100 mmHg are adequate for the baby undergoing TH and SaO2 ≥92% is recommended, PaO2 Levels above 200 mmHg should be avoided.[19],[28],[29]


Although not reported frequently inspiratory stridor is known to occur during hypothermia or after rewarming. Several mechanisms may be responsible; some authors suggest that the glottis mechanics change during hypothermia and during rewarming reflex closure of glottis occurs resulting in stridor, whereas it is also speculated that hypothermia causing capillary leak and larynx edema may be the cause for stridor. Regardless of the mechanisms the stridor observed during or after TH has been easy to resolve with nebulized adrenaline.[30]

  Circulatory Management during Therapeutic Hypothermia Top

Myocardial dysfunction is an expected finding in newborns with HIE due to various factors including decreased contractility as a result of myocardial ischemia, papillary muscle injury, and vasomotor instability.[1],[31] Main effects of TH on the heart are bradycardia usually down to 80-90's /min and decreased cardiac output.[24],[29],[32],[33] The former is mostly sinus bradycardia secondary to the slower activity of atrial pacemaker and intracardiac conduction.

Decreased cardiac output during TH is mostly because of decreased heart rate (HR) but also because of decreased metabolic rate. Therefore blood pressure (BP), peripheral circulation, and particularly cerebral circulation need to be closely monitored during TH and circulatory support should be provided as required. Continuous BP monitoring, capillary refilling time assessments, and urine output are the most frequently used methods. Mean arterial pressure should be kept between 40 and 60 mmHg.[29],[34] Functional echocardiography assessing superior vena cava flow (SVCF), cardiac contractility, cerebral doppler ultrasonography, and near infrared spectroscopy (NIRS) are other methods to follow circulation in these patients. SVCF is particularly important in reflecting cerebral circulation and high levels during TH is considered as loss of cerebral autoregulation and predictor of poor prognosis.[35] The medication to be administered for circulatory support should be based on the echocardiography findings. Effects of medications may be different during TH and during rewarming. Dobutamine and milrinone provide good examples for this; cause increased cardiac output as body temperature increases, therefore, dose adjustments may be required during rewarming.[36],[37]

Biomarkers such as cardiac troponin I, CPK-myocardium bound (CPK-MB), B type natriuretic peptide (BNP)[38] are additional parameters that can be followed during the course of treatment. Both troponin and CPK-MB increase in HIE depending on the extent of injury to the heart and then decrease gradually. TH has been shown to prevent the excessive increase in troponin which can be interpreted as the cardioprotective effect of treatment.[39] Lower levels of BNP in patients undergoing TH also suggest a protective effect of treatment.[38]

Peripheral vasoconstriction and hyperviscosity causing decreased peripheral circulation are other effects of TH in newborns.[40] Hyperviscosity may be partially responsible from PPHN. Lactate is increased in newborns with HIE and may remain high throughout TH however this is interpreted as the severity of hypoxic insult rather than the negative effect of TH on peripheral circulation.[33] Peripheral vasoconstriction or circulatory failure may cause acidosis which should correct itself after circulation is restored by circulatory support, however if PH remains <7.0 for more than 4 h sodium bicarbonate diluted to half strength may be administered over 30–60 min.[28]

  Fluid, Electrolyte and Nutritional Management during Therapeutic Hypothermia Top

Since asphyxiated newborns are prone to ischemic bowel disease and the effect of TH on mesenteric circulation is unclear enteral nutrition is generally delayed until after rewarming [29] or minimal enteral nutrition as 1 cc of breast milk every 6 h is suggested for gut priming during TH [24] making total parenteral nutrition (TPN) the main source of nutrient supply although Azzopardi suggests feeding cautiously after 24 h even during TH.[28] Regardless of enteral feeding TPN should be planned and administered as early as possible. If enteral feeds are administered, a slow and careful increase in volume and careful physical examination for signs of the ischemic bowel is recommended.

Daily maintenance fluid should depend on the individual patient's need for that day based on weight and urine output. Initially 40–60 ml/kg/day of 10% dextrose may be started, and electrolytes and parenteral nutrition components may be added the next day if electrolytes are stable. HIE itself may cause renal failure or syndrome of inappropriate antidiuretic hormone (SIADH) resulting in oligo-anuria which may necessitate fluid restriction to avoid volume overload and brain edema. On the other hand, TH may be associated with a condition called “cold diuresis” which is a well-described entity in the adult population.[41] It is most likely due to nonosmotic suppression of vasopressin during cold exposure. However, this has not been defined in newborns, and in fact the more worried condition in the newborn is fluid retention secondary to kidney injury at the time of hypoxic insult for which some newborns may even require peritoneal dialysis or hemofiltration. Theophylline has been used prophylactically to induce urinary output in small sized studies with promising results.[42] It is best to place a urinary catheter to infants with HIE early on to be able to follow urine output.

Electrolyte monitoring is recommended every 8–12 h in newborns with HIE during the first 24–48 h. Dilutional hyponatremia may occur as a result of fluid retension due to kidney injury, SIADH or as a result of tubular dysfunction. TH may cause intracellular potassium shift which will be reversed during rewarming requiring close follow-up and careful management. Ca and Mg also need to be followed and provided in TPN solution according to daily needs. Hypomagnesemia has been reported during TH despite supplementation in TPN.[43]

Glucose management is of particular importance in newborns with HIE whether or not TH is administered. After the initial perinatal asphyxia, hyperglycemia may occur due to the release of stress hormones followed by hypoglycemia as a result of depleted liver glycogen. Glucose levels should be followed Q 4 hourly until stable and glucose infusion rate should be titrated to maintain normal range. TH may result in hyperglycemia due to decreased metabolic rate. Nonsedated infants may also develop hyperglycemia during TH because of the stress leading to catecholamine and cortisol release.[28],[33]

Protein and lipids are administered in TPN solutions. Two cases have been reported to have elevated triglycerides during TH requiring dose adjustment for lipids.[44]

  Renal Management during Therapeutic Hypothermia Top

Acute kidney injury (AKI) occurs rather frequently following perinatal asphyxia and has been found to be associated with longer duration of hospitalization and ventilator treatment, as well as increased brain injury. It is not easy to define kidney injury in newborn with HIE who undergo TH based on urine output for reasons described above therefore a serum creatinine (sCr) based definition is used. Rise in sCr >0.3 mg/dl or rise of 150–200% is considered as stage I AKI, if the rise is 200–300% of previous sCr it is considered stage II AKI, if the rise is >300% or sCR >2.5 mg/dl or dialysis is required it is defined as stage III AKI based on “modified AKI” criteria.[45] sCr has been shown to continue to increase for 72 h in HIE newborns with AKI undergoing TH [45] and may remain abnormal even at the time of discharge requiring long-term follow-up.

  Hematological Complications Top

HIE is well-known to have effects on the hematological system namely causing increased number of nucleated red blood cells [46] in the circulation and disseminated intravascular coagulation.[34] Prolonged coagulation tests, low platelet counts are expected in newborns with HIE. TH is also known to cause platelet dysfunction, and thrombocytopenia and, in fact, low platelets are one of the two main side effects of treatment the other one being sinus bradycardia. In large scale, multicenter studies thrombocytopenia has been reported more often than control groups, however, has not required treatment cessation. Prolonged coagulation tests may resolve easily with fresh frozen plasma administration [24],[28],[47] however platelet dysfunction may require special attention since plug formation may be impaired despite normal platelet counts.[48] This is particularly important for newborns delivered by assisted delivery who are prone to subdural or subperiosteal hemorrhage and these infants require careful assessment during TH.

On the other hand in one small study TH has been shown to decrease the NRBC in moderate HIE newborns which needs to be kept in mind while following these patients.[46]

One other effect of TH on the hematological system is hyperviscosity which theoretically may be one of the causes of PPHN and slow microcirculation as mentioned above. Careful fluid and circulatory management is sufficient to overcome this effect.

  Infection Control during Therapeutic Hypothermia Top

Infection may be one of the causes of perinatal asphyxia resulting in HIE. Therefore, almost all newborns diagnosed with HIE are started on empirical antibiotic treatment if the cause of asphyxia is not clear. On the other hand, hypothermia is known to cause some degree of immunosuppression with decreased leukocyte number and impaired functions.[49],[50] The fact that TH also causes delayed clearance of certain medications including gentamicin requires caution during antibiotic management of these babies. If the general empirical antibiotic regimen is to be administered gentamicin dosing interval needs to be extended to 36 h.[51] Another possible approach is the administration of third generation cephalosporins namely cefotaxime in place of gentamicin together with ampicillin during TH.[29] It should be kept in mind that there is a delay in cytokine response including IL-6 during TH also resulting in delayed C-reactive protein elevation up until 80 h [49] which may make the physician reluctant to stop the antibiotics.

  Stress and Pain Management during Therapeutic Hypothermia Top

Babies undergoing TH may feel stress and pain, and this may oppose to the neuroprotective impact of TH. It is highly recommended to provide optimal sedation and analgesia during TH.[52] As opposed to adults newborns may not exhibit shivering, therefore, their pain may go unnoticed. Some indirect findings like increased HR due to increased catecholamines may provide clues to recognize stress and pain in these infants. Normally hypothermia should cause a reduction in HR by 10/min with each degree of celcius, and a well-sedated newborn is expected to have HR around 100/min.[53] An HR >110–120/min should warn about inadequate sedation and pain control.[52] Narcotic analgesics like morphine or fentanyl may be used but with caution for the delayed clearance of the drugs both due to impaired hepatic functions and TH in this population. If the baby is not on ventilator pain management may be more challenging for it will require fine titration of the medication to avoid respiratory depression in an already neurologically depressed infant and yet to provide adequate pain relief. Chloral hydrate or low dose narcotic infusion with careful respiratory monitoring is recommended in this subgroup.

  Other Issues Top

Subcutaneous fat necrosis

SCFN has been reported in newborns with difficult delivery or perinatal stress before the era of TH, however after TH came into practice its association with SCFN has been reported. It is a self-limited condition, however, may cause refractory hypercalcemia sometimes resulting in nephrocalcinosis. SCFN usually appears within 1st-week of life (after TH is over), and hypercalcemia may even occur months later after SCFN has resolved necessitating long-term follow-up of newborns who developed SCFN during TH.[54],[55] The occurrence of SCFN has been reported to be reduced by using a gradient variable mode of whole body hypothermia instead of automatic servo controlled mode which presumably allows the skin to accommodate the temperature change with a smooth transition.[56]

Drug metabolism

Hypoxic injury of liver and kidneys are known to occur after perinatal asphyxia affecting drug clearance by these organs. TH also causes delayed metabolism of drugs such as phenobarbital, morphine, and vecuronium by liver due to its effects on cytochrome p450 enzyme systems. There is no consensus about dosing or dosing intervals regarding these medications during TH however literature suggests careful follow-up for toxic effects.[47],[57],[58] Lidocaine is another medication which may be used for seizure control and has been reported to have reduced clearance during TH again necessitating careful monitorization for cardiac effects.[59] Gentamicin metabolism has been studied during TH and 36 h dosing interval has been found to result in acceptable trough levels with desired efficacy.[51],[60] Since hearing loss has been associated with high gentamicin serum levels this may be an acceptable approach if it is to be used.[61]

  Clinical Follow-Up and Monitorization during Therapeutic Hypothermia Top

Careful clinical and laboratory monitorization is essential in newborns with HIE regardless of the mode of treatment and TH requires additional parameters to be followed throughout treatment. Umbilical arterial and venous catheterization for blood draw, BP monitoring and central TPN administration, and urinary catheterization for urine output measurements can be quite helpful. Full monitorization including HR, respiratory rate, BP, core temperature, and SaO2 are required. Core temperature monitorization with esophageal or rectal probe should continue until after rewarming is complete to avoid hyperthermia. The axillary temperature measurements have been reported to give variable data and, therefore, should not be preferred over core temperature measurement methods.[5]

Sarnat staging and Thompson scoring should be performed and documented daily during and at least until 1-week after TH. Overt or subtle seizures may be missed if electroencephalography/aEEG monitorization is not performed. The time the neurological findings have normalized, and normal newborn reflexes are obtained is important to determine long-term prognosis and need to be well-documented. However, the impact of sedatives or antiseizure medications should also be taken into account during neurological assessment since these medications may have longer lasting effects in newborns undergoing TH.

Skin lesions such as scalp edema during selective head cooling, generalized edema during whole body hypothermia should be checked at least every 12 h and SCFN due to hypothermia should be kept in mind even after treatment is over.

Systemic circulation may be impaired due to myocardial dysfunction and microcirculation may be impaired due to hypothermia both needing careful physical examination. Pressure wounds may occur as a result of poor systemic, microcirculation, and immobilization. Ischemic bowel disease should also be kept in mind, and careful abdominal examination should be performed. Abdominal distension and feeding intolerance should be approached cautiously. Daily echocardiographic assessment is helpful to determine cardiac functions and supportive treatment if required.

Daily cranial ultrasound is necessary for the timely diagnosis of possible intracranial hemorrhage which may extend during TH. Cerebral doppler assessments are useful to determine cerebral blood flow and exclude venous sinus thrombosis.[28]

If available aEEG is used both in the decision making for TH in newborns with HIE and during follow-up of treatment. aEEG and MRI during TH are reviewed in other chapters of this issue.

NIRS is used by some centers to follow cerebral oxygenation during TH and if available may provide valuable data regarding cerebral perfusion and prognosis.[62],[63]

Baseline electrolytes, renal and liver function tests, LDH, complete blood count (CBC), coagulation tests, cardiac enzymes, BNP, and troponin should be obtained before starting TH. Renal and liver function tests, CBC, and coagulation tests require at least daily measurements. Electrolytes and platelets need to be followed every 8–12 h during the 1st day and then daily depending on the stability of the levels. Normal platelet count may not always guarantee normal bleeding time for plug formation is impaired during TH. Serum or plasma levels of certain drugs like phenobarbital or gentamicin may need to be followed due to decreased clearance during TH.

  Rewarming: How to Make it Go Smoothly? Top

Most of the effects of TH including bradycardia, reduced cardiac output, and hyperviscosity slowly resolve after rewarming which needs to be performed between 4 and 12 h (0.2–0.5°C/h). Core temperature monitorization should continue for several hours after normothermia to avoid overshooting the rewarming.[52] Platelets may take a few days to come back to normal. The metabolism which has slowed down throughout treatment now gets back to its normal rhythm which may cause recurrence of seizures. Recurrence of seizures may require rewarming to be temporarily stopped or recooling.[64]

Hypotension may occur during rewarming due to peripheral vasodilation and increased blood delivery to peripheral circulation which can be overcome by volume replacement.[24] Apnea may be observed during rewarming and respiratory support may be required.

Electrolytes especially potassium will need to be followed for the intracellular shift will now be reversed. Drug metabolism which has slowed down during TH will also change increasing the clearance of certain medications like seizure medications or opioids which may now have subtherapeutic levels.

Overall close follow-up of clinical or electrical seizure activity, body temperature, circulatory, and respiratory functions is essential during rewarming for timely intervention. Platelets, electrolytes and myocardial enzymes also need to be checked after rewarming to ensure normalization. Patients who develop SCFN require calcium levels checked even after discharge since hypercalcemia may occur months later.

  Summary Top

TH as whole body or selective head cooling has become a standard therapy for moderate-severe HIE to reduce neurological damage. The best neuroprotective effect is obtained if the treatment is started before 6 h of life and even better if started before 3 h. Identification of newborns with moderate to severe HIE may be challenging for some babies may appear mildly affected initially and may progress to a worse stage overtime, but the critical therapeutic window may be missed. Repetitive neurological exam, 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. Sinus bradycardia down to 80–90/min is an expected finding during TH. Patients need to be sedated adequately throughout TH for stress and pain may reduce the neuroprotective effect of treatment. Particular attention should be paid to maintain normocarbia, normoxia, normal blood glucose levels, and normal BP. Electrolytes, liver-renal function tests, CBC and coagulation tests need to be followed at least daily, and abnormalities should be treated accordingly. Thrombocytopenia is another expected finding during TH 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 TH. Additional monitorization and laboratory methods such as aEEG, cranial ultrasound, cardiac echocardiography, and NIRS are helpful to follow cerebral and systemic effects of TH. After 72 h of TH, rewarming should be performed slowly over 4–12 h with core temperature monitorization continued even after rewarming is over to avoid hyperthermia.

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  References Top

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Thayyil S, Shankaran S, Wade A, Cowan FM, Ayer M, Satheesan K, et al. Whole-body cooling in neonatal encephalopathy using phase changing material. Arch Dis Child Fetal Neonatal Ed 2013;98:F280-1.  Back to cited text no. 3
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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. 5
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