选择性头部亚低温治疗新生儿缺氧缺血性脑病安全性临床多中心研究

目的：尽管小规模的临床研究表明亚低温治疗新生儿缺氧缺血性脑病（hypoxic-ischemic，HIE）是安全的，但仍需大规模的临床多中心的研究进一步证明。本研究目的通过临床多中心研究观察选择性头部亚低温治疗新生儿HIE的安全性。方法：入选标准：生后6 h以内；胎龄 ≥36周，体重≥2 500 g；脐动脉血气分析 pH < 7.0或BE ≤-16 mmol·L-1或生后1 min Apgar评分 ≤ 3并持续到5 min仍然 ≤ 5；生后6 h内出现脑病的临床表现或EEG明显异常。排除标准：严重先天性疾病、合并感染、其他原因导致颅内损伤、严重贫血（Hb < 120 g·L-1）。从2002年5月- 2006年2月共收集246例不同严重程度的新生儿HIE，随机分为治疗组（低温治疗）134例和对照组112例。低温组和常温组各失访17例和12例，故有效病例共217例（低温组117例，对照组100例）。低温组生后6 h内开始选择性头部亚低温治疗，维持鼻咽部温度（34±0.2）℃℃，肛温维持在35℃以上,持续72 h，然后自然复温。常温组维持肛温在36～37.5oC。两组均进行心电、血压、经皮氧饱和度、鼻咽部温度和肛温监测。发现心率失常者进行EEG检测。观察主要不良反应包括：死亡率、严重心律失常、静脉血栓或出血、难以纠正的低血压。低温组72 h时检测肝、肾功能和血常规、血电解质、血糖及血气分析。观察可能出现的其他不良反应。结果：低温组和常温组的死亡率分别为17.9％和25％(P＝0.20)，死亡原因中两组均以重度脑病(低温组和对照组分别为：6.8%和7%，P＝0.96)和呼吸衰竭(低温组和对照组分别为：6.8%和6%，P＝0.8)为主；对照组有1例患者出现室性心律失常和DIC；低温组发生DIC和消化道出血患者各1例；两组均未出现难以纠正的严重低血压和大静脉血栓。低温组和常温组发生严重不良反应的概率分别为 1.7％和2％（P＝1.0）。低温治疗期间心率降低，但仅有4例(3.4%)患儿心率低于80次/分钟；两组之间血压、肝及肾功能、电介质、血生化、血气分析及血常规的变化均无显著性差异。结论：选择性头部亚低温结合全身轻度低温72 h治疗足月新生儿HIE是可行的和安全的。

Safety of selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial

Safety of selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial Objective: Although it had been shown that mild or moderate hypothermia is safe in treatment of neonatal hopoxic-ischemic encephalopathy (HIE) in small scaled pilot clinical study, it is necessary to go on multicentre, randomized, controlled trial to verify its efficacy in neonates with HIE. This multicentre randomized trial is to study the safety of selective head cooling (SHC) with mild systemic hypothermia in neonates with HIE. Methods: Infants qualified for the study if they were ≥36 weeks gestation, ≥2500g birth weight, and ≤ 6 h after birth. Cord blood gas pH≤ 7.0 or base deficit ≥16 mmol/L, or Apgar score≤3 at 1 min, continued ≤5 at 5 min. Neurological findings of neonatal encephalopathy included lethargy, stupor, or coma, with one or more of hypotonia, abnormal reflexes, absent or weak suck or clinical seizures. Exclusion criteria were: major congenital abnormalities, head trauma causing major intracranial hemorrhage, infection or severe anemia. 246 term infants from 16 tertiary referral hospitals with various severity of neonatal encephalopathy were randomly assigned to either head cooling (n=134 ) or control group(n=112). In 29 babies follow up was not available (17 in cooling and 12 in control respectively). Thus 217 allocated to head cooling (n=117) and control group (n=100) respectively.In head cooling group, the nasopharyngeal temperature was maintained at 34℃ with rectal temperature maintained at 34-35℃for 72 h, then rewarming spontaneously. In control group, normal rectal temperature was maintained. During study period, the baby in both groups were given monitor on nasopharyngeal temperature, rectal temperature, heart rate, respiration rate, transcutaneous arterial oxygen saturation and blood pressure. Severe adverse events included death, major cardiac arrhythmia, major venous thrombosis or hemorrhage and severe hypotension despite full support. Na+, K+, Ca2+, glucose, GPT, GOT, BUN, Cr, pH and BE were measured at 72h after treatment. Results: The death was not significantly different (17.9% vs. 25% in cooling and control group respectively, p=0.20). The major reason of death was severe HIE ( 6.8% vs. 7% in cooling and control group respectively , p=0.96) and respiratory failure ( 6.8% vs. 6% in cooling and control group respectively , p=0.8) in both groups. There was one neonate with major cardiac arrhythmia and DIC in control group and two neonates with DIC and severe gastrointestinal hemorrhage respectively in SHC group. The rate of severe adverse events was no differences (1.7%vs. 2% in cooling and control group respectively, p=1.0). In SHC group, most neonates had lower heart rates during the period of hypothermia, but only 4 cases (3.4%) HR were below 80 bpt/min. The systolic and diastolic blood pressures were stable, and no difference between SHC and control group. The rate of abnormal renal function, elevated liver enzymes, metabolic acidosis, hypoglycemia, hyperglycemia, hypocalcaemia, hyponatraemia, and hyperkalaemia were no significantly differences between both groups. The average value of white blood cell, platelet, and the rate of thrombocytopenia were no significantly differences between both groups. Conclusions: These data suggests that selective head cooling with mild systemic hypothermia in neonates with HIE was safety during 72 h therapy.