Hypothermia for hypoxic ischemic encephalopathy in infants ≥ 36 weeks

https://doi.org/10.1016/j.earlhumdev.2009.08.015Get rights and content

Abstract

Hypoxic ischemic encephalopathy is a serious condition affecting infants which can result in death and disability. This is a summary of pathogenesis of HIE, animal studies of cooling for hypoxic and ischemic models, human hypothermia trials, and the American Academy of Pediatrics publication on hypothermia for HIE. Hypothermia for neonatal HIE is continuing to evolve as a therapy. Studies, gaps in knowledge and opportunities for research are presented herein.

Section snippets

Background

Perinatal hypoxic ischemic encephalopathy (HIE) is a serious brain injury affecting 0.5–1/1000 live births in the United States on an annual basis. HIE can result in death or serious impairment in survivors. HIE has a variety of causes including acute perinatal events such as uterine rupture, placental abruption, and cord prolapse. Other causes of interrupted uterine and fetal blood flow and or hypoxia can also result in HIE.

Until publication of the COOLCAP (cooling of head with a cap) and

Pathogenesis of HIE

Evaluations of animal models including fetal sheep, newborn mice, rat pups, piglets, and nonhuman primates [2], [3], [4], [5], [6], [7], [9], [12], [13], [15], [16], [23], [24] with timed hypoxic–ischemic injury have been performed and been reviewed [25], [26]. It should be noted that hypoxia and ischemia can be well-controlled in laboratory studies; this is not necessarily the case in infants as the HIE may be acute, chronic or acute imposed on a chronic injury. Once the injury occurs, there

Animal studies of hypothermia and neuroprotection

Animal studies have provided the basic structure for translation into clinical trials. Cooling performed within 90 min up to < 6 h in fetal sheep showed benefit [5], [6], [9], [16]. Studies in other models also show that cooling is beneficial based on pathology, imaging and tests of learning after hypoxic and/or ischemic brain injury [2], [3], [4], [7], [12], [13], [15].

Clinical trials

In 1955 Westin and Einhorning [1] showed that hypothermia was beneficial in perinatal asphyxia. Pilot studies [8], [10], [11], [14], [27], [28] were undertaken largely for feasibility and preliminary safety evaluation. The pilot studies showed short-term safety and feasibility for providing hypothermia and led to large, randomized controlled trials of cooling. Two large trials [17], [18] and a smaller trial [27], [28] were published in 2005, paving the way for translation of experimental

Additional clinical trials

In the Total Body Cooling trial (TOBY) from England [19] infants with moderate-to-severe HIE have been randomized to receive whole body cooling or standard intensive care. Recruitment and follow-up have been completed and preliminary results are beneficial [33]. The trial design features and the entry criteria for the TOBY trial are similar to those of the CoolCap trial [17] except for the method of cooling. Thus, upon completion, the findings from the TOBY trial can be effectively compared

Safety and secondary issues

Secondary outcomes have been published from the large trials. Eicher et al. [28] carefully collected adverse event information in their 66 patient hypothermia pilot study. The hypothermia treated group had more frequent bradycardia and lower heart rate measurements, longer use of vasopressors, higher prothrombin times, lower platelet levels, and higher rates of seizures. The authors state, however, that not all statistically significant adverse events observed with moderate hypothermia are

American Academy of Pediatrics commentary

The Committee on Fetus and Newborn published a commentary [22] in 2006 summarizing available evidence for mild-to-moderate hypothermia for perinatal HIE. At this point in time (2006), uncertainties including ongoing trials and longer-term follow-up (beyond 2 years of age) existed and are still present today. The AAP commentary concluded that if hypothermia is implemented outside of clinical trials, published protocols should be used, infants should have follow-up and parents should be informed

Continued gaps in knowledge

In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, gaps in knowledge remain in this field. Longer-term impact of hypothermia for HIE remains unknown. The COOLCAP and NICHD trial participants are being followed through school age [38], [39]. Results from these longer-term follow-up studies as well as results from the TOBY Trial and ICE Trial will provide more information for evidence-based guidelines for care of infants

Implications for clinical practice

The AAP commentary concluded that based on the available evidence and the known gaps in knowledge at the current time, therapeutic hypothermia, if offered, should be done using one of the published protocols [22]. Appropriate follow-up needs to be in place for infants undergoing hypothermia for HIE. Longer-term follow-up is unknown [22].

Summary and conclusions

HIE can be a lethal or devastating disease. Until the advent of cooling for HIE, there was no therapy other than supportive NICU care. Cooling offers promise. Additional trial results may help to direct care of these critically ill infants. Longer-term follow-up which is underway in two large trials, CoolCap study and NICHD whole body cooling study, may shed light on long-term effects of cooling therapy for HIE.

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