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Randomized clinical trials performed around the world have shown that therapeutic hypothermia reduces death and major neurodevelopmental disability for infants with moderate-to-severe hypoxic ischemic encephalopathy (HIE).1, 2, 3, 4, 5, 6, and 7
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Hypothermia is initiated within 6 hours after birth and continued for 72 hours, with a target temperature of 33°C–34°C for whole-body hypothermia and 34°C–35°C for selective head cooling. Eligible infants were 35 weeks or greater gestational age in 2 trials and 36 weeks or greater or 37 weeks or greater in the remaining trials. A recent systemic review and meta-analysis that included 7 large randomized clinical trials and 1214 newborns showed a reduction in the risk of death or major neurodevelopmental disability (risk ratio [RR], 0.76; 95% confidence interval [CI], 0.69–0.84) and an increase in the rate of survival with normal neurological function (RR, 1.63; CI, 1.36–1.95) at age 18 months.8 The number needed to treat is 7 to prevent 1 case of neonatal death or major disability. Newborns with moderate HIE had a greater reduction in the risk of death or major neurodevelopmental disability at age 18 months (RR, 0.67; 95% CI, 0.56–0.81) when compared to those with severe HIE (RR, 0.83; CI, 0.74–0.92). There was no difference in head vs whole-body cooling. Follow-up at 6 to 7 years of age of the National Institute of Child Health and Human Development (NICHD) Neonatal Network trial participants found that death or an IQ score below 70 occurred in 47% of the hypothermia group compared to 62% of the control group (p = .06).9 This result was not statistically significant; however, hypothermia was associated with a lower death rate without an increase in the rate of severe disability in survivors.
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The recognition of moderate or severe HIE requires a detailed obstetric history, including any acute perinatal event, such as a placental abruption, cord events such as prolapse or complete knot, maternal hemorrhage, uterine rupture, prolonged fetal bradycardia, or nonreassuring fetal heart tracings. Other essential criteria include Apgar score of 5 or less at 10 minutes or the continued need for ventilator support initiated at birth and continued for more than 10 minutes.
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A modified Sarnat neurologic examination is performed to determine eligibility for therapeutic hypothermia unless seizures have been observed. Abnormalities must be identified in at least 3 of the following 6 categories: level of consciousness, spontaneous activity, posture, tone, primitive reflexes, and autonomic nervous system (Table 76-1).
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The laboratory eligibility criteria for therapeutic hypothermia include a pH of 7.0 or less or base deficit of less than 16 mmol/L in an umbilical cord gas or any gas during the first hour after birth. If the pH is between 7.01 and 7.15, base deficit is between 10 and 15.9 mmol/L, or no blood gas is available, additional criteria are required, including an acute perinatal event and 10-minute Apgar score of 5 or less or assisted ventilation for 10 or more minutes.
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Several of the randomized clinical trials required amplitude-integrated electroencephalography (aEEG) with abnormal background activity for study entry; many centers continue to use this eligibility criterion for therapeutic hypothermia.1,4,5
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Other baseline laboratory studies performed in this population include a complete blood cell count (CBC), blood culture, C-reactive protein value, coagulation panel, complete metabolic panel, and creatinine kinase, troponin, and lactate values. Conventional EEG, when performed with video recording, helps with identification of infants with clinical and subclinical seizures.
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Differential Diagnosis
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The following diagnostic categories must be considered when evaluating an encephalopathic infant, particularly in the absence of an acute perinatal event:
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Metabolic disorders
Sepsis
Neuromuscular disorders
Chromosomal disorders and genetic syndromes
Central nervous system malformations or injury (eg, subdural or subgaleal hemorrhage)
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The following are exclusions for treatment:
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Infants with lethal chromosomal or congenital anomalies are usually excluded.
Infants presenting after 6 hours of age are often not cooled as there are few data suggesting benefit. The window for therapeutic hypothermia is not specifically known; however, it is known that neuroprotection is influenced by the timing of therapy.10,11 The NICHD Neonatal Research Network is currently conducting a trial to evaluate the effect of cooling initiated between 6 and 24 hours of age (http://ClinicalTrials.gov, identifier: NCT00614744).
Infants with profound asphyxia are not likely to benefit; however, early identification of these infants is challenging. At this time, no reliable early clinical markers of nonresponse have been identified, and in the absence of this information, therapeutic hypothermia is initiated and later discontinued if other information, such as neurologic examination, EEG, and magnetic resonance imaging (MRI), confirm that the prognosis is poor.
The use of therapeutic hypothermia to treat mild HIE is controversial. Two trials unintentionally enrolled newborns with mild HIE.6,7 Zhou et al found no death or severe disability in the newborns with mild HIE; Jacobs et al reported a sizable rate of death and disability associated with mild HIE.6,7 The latter study did not use a standardized neurologic assessment tool or formally certify the transport personnel who assessed newborns for eligibility. Misclassification of the level of encephalopathy is potentially responsible for the higher-than-anticipated rates of death and disability.
Parental refusal is a cause for exclusion.
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Ethical Considerations and Consent
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Neonatal therapeutic hypothermia has been studied in a specific patient population: near-term infants who are less than 6 hours of age and meet strict criteria for moderate-to-severe HIE. Multiple prospective, randomized, controlled trials have shown improved neurodevelopmental outcomes in infants with HIE who are cooled. Based on the results of these studies, it would be unethical to withhold this treatment from near-term infants with moderate-to-severe HIE.12 Parents must be informed of the availability of this therapy in a timely fashion and offered the option of transfer to another facility if hypothermia is not available at the birth hospital.
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The situation becomes less clear if the patient is identified as a candidate for cooling outside the 6-hour window postbirth, if the infant is less than 36 weeks’ gestational age, or if the neurologic status does not meet the specific criteria used in randomized clinical trials. Because the complications of hypothermia are few, it could be argued that ethically any patient who might benefit from the therapy should be offered treatment, for instance, the infant who qualifies for treatment but does not arrive at a tertiary facility until 7 hours of age or the infant who qualifies for treatment but is 35 weeks’ gestation. Is it ethical to withhold treatment from such patients because they do not meet criteria used in studies? Conversely, is it ethical to treat patients who may not benefit from the therapy? Some centers have chosen only to treat infants who meet the strict criteria followed in the clinical trials; others decide whether to treat on an individual basis. If treatment is offered to infants who do not meet the criteria used in randomized clinical trials, informed parental consent is essential.12
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Another ethical dilemma encountered by centers that offer hypothermia treatment is the potential for delay in outcome prediction. The early sequelae of HIE present during the 72-hour period in which cooling has been shown to be helpful. Cooling can suppress seizures and alter the EEG pattern, confounding the prediction of poor neurologic outcome based on electrographic evidence. Imaging studies such as computed tomography (CT) or MRI are difficult, if not impossible, to obtain in the cooled infant. Cooled patients are often treated with sedatives or narcotics that alter neurologic status. Discussions about prognosis and decisions about continuation of intensive care are often delayed until after the 72-hour treatment window, by which time the cardiorespiratory status of these patients may have improved to such an extent that discontinuation of support is no longer an option. The result can be prolongation of life in a severely damaged infant, greatly altering the options available to parents.13 If during the 72-hour treatment period the prognosis for a severely ill infant becomes hopeless, parents should be informed that they may choose to end hypothermia treatment and consider withdrawal of intensive support.12
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Multiple studies have shown that cooling should begin as soon as possible following a neurologic insult, hence the 6-hour postbirth window used in the clinical trials completed to date. Informed parental consent is mandatory when offering a treatment within the confines of a clinical trial. Obtaining consent within the 6-hour window can be difficult for many reasons and may result in nontreatment because of lack of consent. Because hypothermia is considered by many to be standard of care for moderate-to-severe HIE in the first 6 hours of life, consent is not routinely required. In fact, failure to treat based on lack of consent could be viewed as unethical. Outside a study protocol, treatment should be initiated within the 6-hour window, with the intent of informing the parents and reaching agreement about treatment as soon as possible.12
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Monitoring for Treatment
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Intensive Care Monitoring
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Infants with neonatal encephalopathy are at risk for multiorgan failure. These infants should be cared for in a level III neonatal intensive care unit (NICU) that can provide intensive monitoring and cardiorespiratory support, correction of metabolic disturbances, treatment of seizures, access to neuroimaging, and consultation with pediatric neurology.
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The CBC with platelet count; coagulation panel; chemistries, including liver enzymes; and lactate should be monitored.
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Although no increased risk for bleeding has been seen in the randomized controlled trials of hypothermia therapy, changes in hematologic parameters are evident with cooling. Lower platelet counts, abnormalities of platelet activation and aggregation, and delayed activation of the fibrinolytic system have been reported.
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Temperature Correction
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Blood gas equipment is calibrated to analyze a sample at a “typical” patient body temperature, generally 37°C. Two of the early trials of hypothermia recommended that blood gases run on cooled patients should be performed on an instrument calibrated to the core temperature.1,3 In an evaluation of the iStat® instrument (Abbott Point of Care, Princeton, NJ), blood gases from patients cooled to 33.5°C were 15% lower on the corrected instrument than on the instrument calibrated to 37°C, and pH was 15% higher (Sheehan, personal communication). Failure to monitor ventilation with an instrument calibrated to the appropriate temperature in hypothermic patients can result in nontreatment of hypocarbia and alterations in cerebral blood flow.
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Avoidance of Hypocarbia
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Pappas et al explored the association of hypocarbia and outcome and concluded that death and disability was increased with longer cumulative exposure to carbon dioxide levels below 35 mm Hg.14
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Electroencephalography
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It is unknown whether seizures result in brain injury or if their presence signifies an underlying brain disorder. It also remains unclear whether treatment of seizures provides neurodevelopmental benefit. Studies have shown an association between neonatal seizures and neurologic deficits.15,16 Glass et al compared the neurodevelopmental outcomes of infants who had HIE and seizures with those of infants who had HIE alone and found infants with HIE and seizures had more adverse neurologic outcomes.17 They concluded that clinical neonatal seizures and their treatment are associated with adverse cognitive and neuromotor outcome and speculated that seizures impair the developing brain. The available evidence supports routine EEG or aEEG monitoring of infants who qualify for cooling, as well as treatment with antiepileptics when seizures are detected.
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Therapeutic hypothermia may alter the pharmacokinetics and pharmacodynamics of drugs used in critically ill newborns with HIE. Some drugs have reduced clearance, longer elimination half-life, and a smaller volume of distribution when used during cooling, related to the decline in function of the cytochrome P450 enzyme system and other physiologic adaptations to low temperature. Drugs known to be affected by hypothermia include morphine, midazolam, fentanyl, vecuronium, phenytoin, phenobarbital, and gentamicin.18
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Sedation and Pain Control Considerations
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Pain and discomfort can be challenging to assess in cooled newborns as the majority are encephalopathic and do not exhibit the usual indicators of pain. Some cooled infants will demonstrate signs of stress with grimacing, crying, and shivering. Because most patients develop sinus bradycardia while cooled, a heart rate in the normal range may be an indicator of pain. Elevated cortisol levels were reported in cooled animals as compared to normothermic controls.19 Furthermore, in the same animal model, hypothermia without sedation failed to provide neuroprotection.19 The authors speculated that inadequate sedation of infants undergoing hypothermia may block the protective effects of hypothermia.
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Therapeutic hypothermia can be achieved using passive or active cooling methods. The ideal method achieves the desired temperature quickly, maintains that temperature without fluctuation, and avoids over- and undercooling during the initiation and rewarming phases.
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Passive cooling is defined as withholding of external heat sources. The isolette or warmer is turned off, and no blankets or clothes are used. The temperature is monitored manually, and heat is provided if the patient becomes too cold. This method of cooling is frequently associated with profound overcooling and great fluctuations in temperature.20, 21, 22, and 23
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Active cooling employs devices such as water- or gel-filled mattresses, fans, and gel or water pillows. Active cooling methods may be manual, with adjustments to devices made by the caregiver, or servo controlled, with the patient temperature regulated by an electronic temperature probe with a feedback mechanism to the cooling device. Compared to adults, infant body temperature is more responsive to conductive heating and cooling because of a higher ratio of skin contact area to body mass. Servo-controlled cooling is superior to manually controlled cooling with respect to avoidance of over- and undercooling and fluctuations in core temperature.24
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Active servo-controlled cooling has been studied in newborns with HIE using several different methods, including selective head cooling, whole-body cooling, and servo-regulated fan. Selective head cooling utilized a servo-regulated, water-filled, fitted cooling cap attached to a heating/cooling unit (Olympic Medical Cool Care System, Olympic Medical, Seattle, WA). It was used in conjunction with a radiant warmer to maintain a core rectal body temperature of 34°C–35°C. Studies of newborns with moderate-to-severe encephalopathy demonstrated a neuroprotective benefit from mild hypothermia achieved with selective head cooling.1,6 A servo-controlled fan was designed to provide an inexpensive and safe method of delivering whole-body hypothermia to infants with HIE. This technique, which uses a fan directed cephalocaudally over the infant and a radiant warmer to control core temperature, was successful in cooling patients without overshoot or significant temperature variability.25
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Whole-body cooling with a water-filled blanket system is the most extensively used and studied of the techniques currently available for hypothermia in newborns. The radiant warmer is turned off, and cooling to 33°C–34°C is achieved using a water-filled blanket, esophageal or rectal temperature probe, and servo-controlled heating/cooling unit. The devices available in the United States suitable for use in newborns are the CritiCool® (Mennen Medical, Southampton, PA) and the Blanketrol® system (Cincinnati Sub-Zero, Cincinnati, OH).
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Whole-Body Cooling Using the Blanketrol System
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The Blanketrol II and III are used to control patient temperature through conductive heat transfer. Both devices contain a heater, compressor, circulating pump, and microprocessor board. For initiation and maintenance of hypothermia and for rewarming, the servo-regulated mode is used with the Blanketrol II. The Blanketrol III can be used like the Blanketrol II for maintenance and rewarming in standard servo mode or by utilizing a software program called Gradient Control to minimize fluctuations in water temperature. With either system, an infant-size blanket is placed under the patient and water is continuously circulated between the Blanketrol heater/cooler unit and the blanket. A probe is placed in the esophagus or rectum for servo-regulation of patient temperature. When using the Blanketrol in standard servo mode, a second larger blanket added to the cooling circuit will act as a heat sink and damp patient temperature fluctuations that occur when only the small neonatal-size blanket is used. The current standard of care is to cool to a temperature of 33°C–34°C and maintain this temperature for 72 hours. Rewarming is done slowly, increasing the temperature by 0.5°C per hour. Care should be taken to avoid rapid rewarming and hyperthermia. Patients should be monitored closely as seizures and hypotension can occur during, and in the hours following, rewarming.
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Infants Who Are Slow to Rewarm
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Many infants will not reach normothermia in the initial 7-hour rewarming period, and some may take up to 24 hours. The Blanketrol system should remain in place with the temperature set to 37°C degrees. The radiant warmer should remain off. The system should be checked to make sure it is functioning properly, and the environment should be checked for drafts. If after 24 hours of rewarming, normothermia has not been achieved, the Blanketrol system can be discontinued and the final warming done slowly using the radiant warmer, being careful not to exceed a warming rate of 0.5°C per hour.
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Hypothermia on Extracorporeal Membrane Oxygenation
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Selected patients on extracorporeal membrane oxygenation (ECMO) may also meet the criteria for therapeutic hypothermia. All ECMO systems include a heating/cooling device that is used to control blood temperature in the extracorporeal circuit. This can be used to provide therapeutic hypothermia by setting the device to cool the patient to the desired temperature and manually adjusting based on a core temperature reading. The ECMO heater displays fluid temperature (circuit blood temperature), but this reading does not accurately reflect core body temperature and should not be used to servo control cooling during hypothermia treatment. Esophageal or rectal temperatures can be used to monitor the hypothermia patient on ECMO, but care must be taken with use of these probes because of systemic heparinization during extracorporeal bypass.
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Hypothermia During Neonatal Transport
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Initiation of hypothermia must occur within 6 hours of birth for optimal neuroprotection. The 6-hour window is easily achieved when an infant is born at a level III NICU; however, the majority of the infants in the large randomized trials were outborn and required transport to a setting where therapeutic hypothermia could be provided. In the 3 randomized trials that performed cooling in transport, there were limited data or discussion of the specific implementation, temperature profiles, or outcomes of infants cooled in transport.2,4,7
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Many cooling centers have chosen to offer cooling during transport by withholding external heat sources (passive cooling) or by using ice/gel packs (active cooling).26 Despite careful attention to temperature management in transport and the development of clinical protocols, the temperatures achieved during transport are not consistently in the target range (33°C–34°C).20, 21, and 22 Until recently there were no portable servo-regulated cooling devices approved by the Food and Drug Administration (FDA) for use during transport in the United States. The Tecotherm Neo (Inspiration Healthcare, LTD, Leicester, UK), a small, portable, servo-regulated cooling device with continuous core temperature monitoring, is now approved for use.
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Temperature Monitoring
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During cooling, the minimal standard for temperature monitoring is a core temperature measurement every 15 minutes for the first 4 hours, every hour for the next 8 hours, and every 4 hours during the remaining period of hypothermia treatment.27 The goal of hypothermia treatment is to cool the brain temperature to 33°C–34°C. Because brain temperature cannot be directly monitored at the bedside, esophageal or rectal temperatures are routinely used as surrogates. In a study of patients undergoing deep hypothermia during cardiopulmonary bypass, with brain temperature measured directly with a thermocouple embedded in the cerebral cortex, esophageal temperature was found to be a better approximation of brain temperature than nasopharyngeal, rectal, pulmonary artery, bladder, or axillary measurements.28 Skin temperature as a proxy for core temperature was studied; a wide discrepancy between skin and rectal temperatures was seen.22 Landry et al compared simultaneous axillary and rectal temperature measurements and found a wide variability at all stages of cooling.29
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Overcooling is seen with non–servo-regulated cooling, particularly during transport. It can lead to “cold-injury syndrome,” which is associated with body temperature below 34°C and is characterized by increased mortality, sclerema, renal failure, pulmonary hemorrhage, disseminated intravascular coagulation (DIC), hypoglycemia, electrolyte and acid-base disturbance, increased risk of infection, and cardiac complications.30
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Elevated body temperature may occur during rewarming or after hypothermia is discontinued. It is important to be aware that elevated body temperature has been associated with exacerbation of the brain injury caused by HIE.31,32 For this reason, it is imperative that patients be rewarmed slowly, no more than 0.5°C hourly, and that body temperature be monitored frequently in the postcooling period.
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Infants must remain supine. Rolls should be placed under the blanket for nesting, bringing it up around the sides of the infant and under the legs, increasing the surface area in contact with the blanket.
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Most cooled infants develop benign sinus bradycardia, with heart rates between 60 and 100 beats per minute. Heart rates above 120 beats per minute may be a sign of pain or stress in the cooled infant.
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Therapeutic hypothermia has not been associated with hypotension. A multicenter, randomized, controlled study showed that mild systemic hypothermia did not affect arterial blood pressure or the need for inotropes or volume in infants with moderate-to-severe encephalopathy.33
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In the cooled infant, perfusion of the skin may be decreased by perinatal asphyxia and further decreased by hypothermia. Cooled patients may exhibit skin changes, including cyanosis, erythema, and sclerema. More rarely, patients may develop subcutaneous fat necrosis, which usually presents several days or even weeks after discontinuation of cooling therapy.34,35 Skin complications may be lessened by patient positioning, such as tilting side to side to avoid constant pressure on the back during cooling. Avoidance of overcooling may be protective of skin integrity. Filippi et al studied 39 infants cooled with the Blanketrol III system and compared the automatic temperature control mode to the gradient control mode.36 Two of the 11 infants cooled in the automatic mode developed skin complications consistent with subcutaneous fat necrosis; none of the 28 infants treated with the gradient control mode developed skin complications. The gradient control mode may be superior because of fewer temperature fluctuations.
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Hypercalcemia is a potentially lethal complication of subcutaneous fat necrosis.37 The etiology is uncertain but may involve production of nonrenal 1, 25(OH)2D3 from the skin lesions. It may present at the same time as the skin lesions or up to 6 months later. Treatment includes limiting calcium and vitamin D ingestion, hydration, and diuretics. Any infant with the diagnosis of subcutaneous fat necrosis posthypothermia should have serum calcium levels followed regularly in the first 6 months of life.
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Infants who qualify for hypothermia are often critically ill. Despite intensive care, their condition may deteriorate, and a decision may be made to discontinue support. The timing of this decision should not be affected by a desire to complete the therapeutic hypothermia treatment regimen.
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