Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI)

ABSTRACT: BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2--3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS: Term newborns (gestational age >= 36 weeks and birth weight >= 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns. Trial registration Current Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25.     

Hypothermia reduces neurological damage in asphyxiated newborn infants

BACKGROUND: Perinatal asphyxia remains one of the most devastating neurologic processes. There is experimental and clinical evidence that cerebral cooling may suppress the biochemical cascades leading to delayed cerebral damage. OBJECTIVE: To determine if hypothermia started soon after delivery reduces cerebral damage in term infants. DESIGN/METHODS: Retrospective chart analysis with historical controls. Ten asphyxiated newborns treated with hypothermia between October 1998 and October 1999 were compared to 11 asphyxiated newborns admitted from September 1997 to September 1998. Characteristics at birth of infants of the two groups (control and hypothermia) were comparable. After obtaining parental consent, whole-body hypothermia was induced before the 6th hour of life by placing a cold blanket (Polar Air, Augustine Medical Inc., model 600) around the body of the patients. Rectal temperature was maintained between 32 and 34 degrees C for 72 h. Outcome was assessed by neurological evaluation at birth and every 3 months up to the 12th month. Brain MRI was performed in the 2nd month. We had no evidence of severe adverse events related to hypothermia. In the hypothermic group there was a significant (p < 0.05) reduction of major neurologic abnormalities at follow-up and abnormal MRI findings. CONCLUSIONS: Hypothermia appears to be safe. Our results on morphological damage evaluated by brain MRI and neurological outcome are encouraging: randomized controlled trials are needed to confirm this experience.     

Temperaturregulationsstörungen im Kindesalter

Background

The danger of heatstroke or accidental hypothermia is usually underestimated when risk situations are not appreciated in the clinical routine. This may cause preventable morbidity, e.g. postnatal or perioperative hypothermia or hyperthermia in adolescent athletes, in dehydration or in drug fever.

Treatment

Therapy includes not only restoration of normothermia but also correction of the pathophysiological derangement especially in hypothermia with suspended animation and in heatstroke with multiple organ dysfunction syndrome. Hypothermia or hyperthermia may also emerge as part of an underlying disease in which situation the optimal body temperature needs to be discussed. Normothermia appears to be rational if abnormal body temperature is associated with outcome, e.g. hypothermia in sepsis, trauma or cardiac failure and hyperthermia after perinatal asphyxia, stroke, intracerebral bleeding or head trauma. New evidence shows, however, that abnormal body temperature may also contribute to a better treatment outcome in certain diseases, such as fever for infection or active cooling for encephalopathy after perinatal asphyxia or after cardiac arrest.     

Diagnose und Behandlung der perinatalen Asphyxie

Perinatal asphyxia has its origin at the time of delivery and is defined as the presence of severe metabolic acidosis with a pH ≤7.0 and a base deficit ≤-12 mmol/l in an arterial blood sample taken immediately after birth in association with organ dysfunction. The most severe complication following neonatal asphyxia is the development of hypoxic-ischemic encephalopathy. The application of controlled hypothermia aims at reducing the risk of long-term sequelae arising from this complication and should be performed according to the recommendations of large clinical trials by a specialized perinatal center. As the presence of distinct criteria and imaging results are of prognostic value, monitoring of these patients should include these diagnostics and documentation of the respective clinical variables. Long-term follow-up of neurologic development are recommended.     

Myelomeningocele: prenatal diagnosis,pathophysiology and management

Myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of the child with spina bifida. Postnatal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. In utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. Early fetal intervention may improve neurologic outcome and reduce the hindbrain herniation associated with the Arnold-Chiari II malformation. These changes may improve long-term neurologic function and limit requirements for shunt placements and other surgical interventions. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in utero intervention. A prospective, randomized clinical trial is planned comparing prenatal MMC repair with postnatal repair.     

Cerebral hypothermia for prevention of brain injury following perinatal asphyxia

The possibility that hypothermia has a therapeutic role during or after resuscitation from severe perinatal asphyxia has been a longstanding focus of research. Early studies using short periods of cooling had limited and contradictory results. We now know that resuscitation can be followed by a "latent" phase, characterized by transient recovery of cerebral energy metabolism, before secondary deterioration occurs with seizures, cytotoxic edema, and cerebral energy failure 6 to 15 hours after birth. Recent experimental studies have shown that moderate cerebral hypothermia initiated as soon as possible in the latent phase, before the onset of secondary injury, and continued for 48 hours or more is associated with potent, long-lasting neuroprotection. These encouraging results must be balanced against the well-known adverse systemic effects of hypothermia. Randomized clinical trials are in progress to test the safety and efficacy of cerebral hypothermia.     

How much of neonatal encephalopathy is due to birth asphyxia?

In the literature on neonatal encephalopathy, the pervasive assumption is that once infants with major malformations or infections have been excluded, most of the remaining cases are due to birth asphyxia. Assessing the proportion of neonatal encephalopathy that is due to asphyxia during birth is difficult because of problems in defining asphyxia and neonatal encephalopathy and in recognizing the cause of neonatal neurologic illness. Available evidence indicates that neonatal neurologic signs are not strongly related to obstetric complications, signs of fetal distress, or biochemical markers usually considered to indicate perinatal asphyxia. Most studies that have sought positive evidence of independent markers of intrapartum asphyxia have found them to be absent in a large majority of neurologically symptomatic neonates. We conclude that the proportion of neonatal encephalopathy that is asphyxial in origin is not known but warrants examination, especially in view of the probable need in the near future to identify, on the basis of evidence available in the first hour or so of life, suitable candidates for clinical trials of powerful but risky treatments of birth asphyxia.     

Perinatal corticosteroids: A review of research. Part I: Antenatal administration

The premature infant may receive therapeutic glucocorticoid drugs while in utero or in the postnatal period. This article (part I of a two-part series) discusses the benefits and risks of in utero, or antenatal, corticosteroids (ACS) for the premature infant. Part II addresses the benefits and risks of postnatal corticosteroid (PCS) use. There are numerous clinical studies on the therapeutic use of these steroids for the prevention of respiratory distress syndrome and chronic lung disease in the premature infant, although research results on the efficacy of repeated steroid exposure among premature infants vary. Premature infants who are exposed to repeated courses of ACS and/or high-cumulative-dose PCS may show no neurologic side effects until later in life. Research in newborn animal models focused on the timing, duration, and amounts of ACS and PCS. Current clinical research includes examination of the neurodevelopment of infants who are therapeutically exposed to perinatal corticosteroids, to identify safer minimal dose protocols. Over the past 30 years, corticosteroids have been increasingly prescribed before and after birth. Understanding the potential treatment benefits and risks to human fetuses and neonates is vital to clinical practice. This review presents historic and pharmacokinetic information about prenatal use of corticosteroids. It also offers scientific evidence of the benefits and risks identified in animal models and clinical trials, to stimulate thought that gtiides neonatal clinical practice.     

Subcutaneous fat necrosis after moderate therapeutic hypothermia in neonates

Therapeutic moderate hypothermia in newborns with hypoxic-ischemic encephalopathy is rapidly becoming standard clinical practice. We report here 12 cases of subcutaneous fat necrosis among 1239 cases registered with a national registry of newborns treated with moderate whole-body hypothermia. All the infants suffered from perinatal asphyxia and hypoxic-ischemic encephalopathy. Moderate-to-severe hypercalcemia was identified in 8 of 10 infants with blood calcium measurements. In all cases the skin lesions appeared after completion of the cooling treatment. Our data suggest that prolonged moderate hypothermia is an actual risk factor for subcutaneous fat necrosis. Because the lesions often develop several days after birth, physicians need to be aware of this condition as a possible complication in infants treated with moderate hypothermia after asphyxia. Blood calcium levels need to be monitored in affected infants.     

Ethical and practical issues relating to the global use of therapeutic hypothermia for perinatal asphyxial encephalopathy

In intensive care settings in the developed world, therapeutic hypothermia is established as a therapy for term infants with moderate to severe neonatal encephalopathy due to perinatal asphyxia. Several preclinical, pilot and clinical trials conducted in such settings over the last decade have demonstrated that this therapy is safe and effective. The greatest burden of birth asphyxia falls, however, in low- and middle-income countries; it is still unclear whether therapeutic hypothermia is safe and effective in this context. In this paper, the issues around treatments that may be proven safe and effective in the developed world and the caution needed in translating these into different settings and populations are explored. It is argued that there are strong scientific and ethical reasons supporting the conduct of rigorous, randomised controlled trials of therapeutic hypothermia in middle-income settings. There also needs to be substantial and sustainable improvements in all facets of antenatal care and in the basic level of newborn resuscitation in low income countries. This will reduce the burden of disease and allow health workers to determine rapidly which infants are most eligible for potential neuroprotection.     

Asphyxie périnatale à terme : diagnostic,pronostic, éléments de neuroprotection

Birth asphyxia occurs in 0.5% of term deliveries. Prognosis of newborns with birth asphyxia depends on clinical features of neonatal encephalopathy. The outcome of infants without encephalopathy is excellent. In contrast, neurological outcome of infants with encephalopathy is poor: 40 to 100% of neurodevelopmental disabilities according to the grade of encephalopathy. Prognosis can be more accurately assessed by EEG and MRI. Infants with encephalopathy following birth asphyxia must be referred as soon as possible in centers where neuroprotection by hypothermia is available.     

PERINATAL ASPHYXIA AND RESIDUAL PLACENTAL BLOOD VOLUME

The present data suggest that perinatal asphyxia may result in a transfer of blood, in utero, from placenta to fetus. The data contain no suggestion that asphyxia causes pooling of fetal blood in the placenta.     

Environmental cooling of the newborn pig brain during whole‐body cooling

Aim: Therapeutic hypothermia after perinatal asphyxia decreases brain injury in newborns, whereas hyperthermia worsens the brain injury. We examined how different clinical practices influence regional brain temperatures during hypothermia. Methods: Six newborn pigs, which have comparable physiology and brain maturation to human term infants, were maintained at hypothermia (33.5°C) or normothermia with a servo‐controlled whole‐body cooling device that is in clinical use. Pigs were anesthetized and fully instrumented for cardiovascular and temperature (rectal and regional brain) monitoring. Changes in brain temperatures were measured during four different paradigms to mimic different clinical practices. Results: Inserting an insulating pillow between the head and the heated surface reduced cortex temperature by 1 or 2°C during normothermia (core temperature T_core 37°C) or hypothermia, T_core 33.5°C. Reducing ambient temperature from 28°C to 23°C reduced cortex temperature by 3.9 ± 1.9°C. Without a hat and overhead heater at normothermia, cortex and deep brain temperatures were reduced by 1.2 ± 0.8 and 0.7 ± 0.7°C, respectively. Direct overhead heating abolished the normal cortex to deep brain temperature gradient that was maintained if using a head shield. Conclusion: Brain temperature may differ from core temperature during therapeutic hypothermia influenced by different clinical practices.     

Hyperammonemia associated with perinatal asphyxia.

Twelve infants with severe perinatal asphyxia were found to have elevated blood ammonia levels (302 to 960 microgram/100 ml). In the seven survivors, hyperammonemia was associated with CNS irritability, hyperthermia, hypertension, and wide neonatal heart rate oscillations. Follow-up examinations revealed severe neurologic dysfunction in five of seven infants. CNS depression, hyperthermia, hypertension, and a nonreactive, fixed heart rate characterized the infants that died. These findings suggest a clinical entity secondary to perinatal asphyxia whose signs and symptoms may be related to hyperammonemia.     

Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep.

Prolonged cerebral hypothermia is neuroprotective if started within a few hours of hypoxia-ischemia. However, delayed seizure activity is one of the major clinical indicators of an adverse prognosis after perinatal asphyxia. The aim of this study was to determine whether head cooling delayed until after the onset of postasphyxial seizures may still be neuroprotective. Unanesthetized near-term fetal sheep in utero received 30 min of cerebral ischemia induced by bilateral carotid artery occlusion. Eight and one-half hours later, they received either cooling (n = 5) or sham cooling (n = 13) until 72 h after the insult. Intrauterine cooling, induced by circulating cold water through a coil around the fetal head, was titrated to reduce fetal extradural temperature from 39.4+/-0.1 degrees C to between 30 and 33 degrees C. Cerebral ischemia led to the delayed development of intense epileptiform activity from 6 to 8 h postinsult, followed by a marked secondary rise in cortical impedance (a measure of cytotoxic edema) and in carotid blood flow. Cerebral cooling markedly attenuated the secondary rise in impedance and reduced carotid blood flow (p < 0.001). After 5 d recovery, there was no significant difference in loss of parietal EEG activity relative to baseline in the hypothermia compared with the control group (-12.5+/-1.4 versus -15.2+/-1.2 dB, mean +/- SEM, NS) or in parasagittal cortical neuronal loss (82+/-9 versus 90+/-5%, NS). In conclusion, delayed prolonged head cooling begun after the onset of postischemic seizures was not neuroprotective. These data highlight the importance of intervention in the latent phase, after reperfusion but before the onset of secondary injury.     

The 'pharmacology' of neuronal rescue with cerebral hypothermia

The neuroprotective effects of hypothermia during cerebral ischaemia or asphyxia are well known. Although, in view of this, the possibility of a therapeutic role for hypothermia during or after resuscitation from such insults has been a long standing focus of research, early studies had limited and contradictory results. Clinically and experimentally severe perinatal asphyxial injury is associated with a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase with seizures, cytotoxic edema, accumulation of cytotoxins, and cerebral energy failure from 6 to 15 h after birth. Recent studies have led to the hypothesis that changes in post-ischaemic cerebral temperature can critically modulate encephalopathic processes which are initiated during the primary phase of hypoxia-ischaemia, but which extend into the secondary phase of cerebral injury. This conceptual framework allows a better understanding of the 'pharmacological' parameters that determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate cerebral hypothermia initiated in the latent phase, between one and as late as 6 hours after reperfusion, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. These encouraging results must be balanced against the adverse systemic effects of hypothermia. Randomised clinical trials are in progress to establish the safety and efficacy of prolonged cerebral hypothermia.     

Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants.

Twenty-eight term neonates with severe perinatal asphyxia were referred to a tertiary neonatal intensive care unit (NICU). The morbidity of asphyxia included involvement of the pulmonary (n = 24 infants), central nervous system (n = 22), renal (n = 15), cardiac (n = 14), metabolic (n = 13) and hematologic (n = 10) systems. The majority of neonates had more than three organ systems involved. Twenty-four neonates survived the neonatal course and at NICU discharge all system effects other than the central nervous system had resolved. At 5 years (60 months), 14 children had a normal neurologic examination, 9 had spastic quadriplegia and one had hemiplegia. Nine children had a McCarthy General Cognitive Index (GCI) greater than or equal to 84, 3 had a GCI between 68 and 83 and 12 scored less than 67. Neonatal seizures, renal problems, microcephaly at 3 months, and post-neonatal seizures were associated with an abnormal neurologic outcome or a GCI less than 67. A neurologic examination during the first year of life may reveal whether children with birth asphyxia will be relatively normal at age 5 years or whether they will show considerable delay.     

Clinical aspects of induced hypothermia in full term neonates with perinatal asphyxia

Moderate hypothermia is a novel neuroprotective therapy for full term neonates with severe perinatal asphyxia. Although the therapy appears to be safe, admission to a level III neonatal intensive care unit of these patients is justified. Potential complications include hypotension, tube obstruction due to sticky secretions, severe bradycardia, and thrombocytopenia. Furthermore, doses of commonly used drugs such as sedatives, anticonvulsants and antibiotics should be adjusted during hypothermia and on rewarming, and should be monitored carefully. Further studies aiming at optimizing onset, duration, and depth of hypothermia in neonates are necessary. Combination of hypothermia with drugs may further improve neuroprotection in asphyxiated full term neonates.     

亚低温治疗新生儿缺氧缺血性脑病临床效果的Meta分析

目的总结国内外亚低温治疗新生儿缺氧缺血性脑病（HIE）的研究结果,采用Meta分析方法评价亚低温治疗HIE的临床疗效,探讨亚低温治疗HIE的可行性。方法制定原始文献的纳入标准、排除标准及检索策略,检索PubMed、EMBASE、Ovid、Springer、中国期刊全文数据库、万方数据库及维普中文科技期刊数据库等,获得亚低温治疗HIE的相关文献。使用Cochrane中心推荐的方法进行文献质量评价,采用RevMan 4.22软件对满足纳入标准的有关亚低温治疗HIE的RCT文献进行Meta分析。以病死率、严重神经系统发育障碍（脑瘫、发育迟缓、失明和听力损害）发生率和不良反应发生率作为观察指标,进行定性和定量综合评估。结果共检索到846篇文献,符合纳入标准的9项RCT研究（16篇文献）进入Meta分析,纳入研究均未采用盲法,文献质量评价7项RCT研究为A级,2项为C级,漏斗图检验提示无发表偏倚。Meta分析结果显示,亚低温组和对照组比较：病死率显著降低（RR=0.73,95%CI：0.58~0.91）;随访至18月龄时严重神经系统发育障碍发生率显著降低（RR=0.70,95%CI：0.53~0.92）;脑瘫发生率显著降低（RR=0.72,95%CI：0.53~0.98）;发育迟缓（RR=0.73,95%CI：0.53~0.99）、失明（RR=0.57,95%CI：0.30~1.08）和听力损害（RR=1.52,95%CI：0.71~3.25）发生率差异无统计学意义;不良反应发生率：窦性心动过缓（RR=6.35,95%CI：2.16~18.68）和PLT减少（RR=1.55,95%CI：1.14~2.11）发生率升高,需要治疗的心律失常、凝血功能异常导致的血栓或出血、脓毒症和惊厥发生率差异无统计学意义。结论亚低温治疗可降低HIE患儿的病死率,改善神经系统发育障碍,且具有较好的安全性。     

Prevention of post-asphyxial hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy is the neurologic sequela of severe birth asphyxia. This review focuses upon the etiology, pathogenesis, clinical manifestations, treatment, and potential preventability of this problem. The clinician must be aware of the underlying asphyxial conditions and anticipate the likely neurologic complications in order to improve the outcome of affected infants.