谷氨酰胺双肽对接受造血干细胞移植患儿肠道保护作用的临床研究

目的研究谷氨酰胺双肽N（2）-L-alanyl—L—glutamine；dipeptide grutamine；dipeptiven，DPT]对造血干细胞移植（hematopoietic stem cell transplantation，HSCT）患儿并发症及恢复的影响。方法选取2004年3月至2007年11月，在中山大学附属第二医院儿科接受造血干细胞移植的56例患儿为研究对象，将其按疾病种类作分层抽样分为谷氨酰胺双肽组（DPT组，n=28）和对照组（n=28）（本研究遵循的程序符合本院人体试验委员会所制定的伦理学标准，得到该委员会批准，分组征得受试患儿监护人的知情同意，并与其签署临床研究知情同意书）。DPT组患儿除接受全胃肠外营养（total parenteral nutrition；TPN）支持外，每天给予谷氨酰胺双肽，剂量为1．5mL／（kg·d），共计21d。对照组采用不含谷氨酰胺（glutamine，Gln）的全胃肠外营养支持。检测DPT组和对照组应用谷氨酰胺双肽前1天、第7、第14、第21天患儿体重、肝功生化、血常规，并对造血干细胞植入和移植后30d内并发症发生情况进行分析。结果DPT组发生肠炎为12例，对照组为26例，两组比较，DPT组发生率低于对照组，且差异有显著意义（P〈0．05）。DPT组患儿的腹泻、腹痛、呕吐、口腔溃疡持续时间，腹泻、腹痛、呕吐次数均短于或少于对照组，两组比较，差异有显著意义（P〈0．05）。两组患儿发生鹅口疮、肛裂等持续时间比较，DPT组短于对照组，且差异无显著意义（P〈0．05）。DPT组患儿长期发热（≥14d）为2例，对照组为10例，两组比较，DPT组的发热总持续时间、最长持续发热时间短于对照组，平均每天最高体温低于对照组，且差异有显著意义（P〈0．05）。DPT组患儿发生口腔溃疡为14例、鹅口疮为4例、肛裂为3例、血真菌培养呈阳性为0例、血细菌培养呈阳性为6例，而对照组分别为19例、5例、1例、1例和7例，两组比较，差异无显著意义（P〉0．05）。DPT组患儿静脉应用抗生素时间为（20．0±7．1）d、入无菌层流室治疗时间为（20．2±6．7）d，对照组分别为（25．4±6．4）d和（24．1±6．9）d，两组比较，差异有显著意义（P〈0．05）。DPT组造血干细胞植入成功为22例，对照组为21例；DPT组发生肠道急性移植物抗宿主病（acute graft versus host disease，aGVHD）为3例、肝静脉闭塞病（venous occlusive disease，COD）为0例，对照组分别为5例和1例，两组移植成功率和肠道急性移植物抗宿主病、肝静脉闭塞病发生率方面比较，差异无显著意义（P〉0．05）。DPT组白细胞（white blood cell，WBC）植入时间为（15．3±5．1）d，血小板（plateiet，PLT）植人时间为（29．0±14．4）d，对照组分别为（16．2±5．8）d和（32．5±18．6）d，两组比较，差异无显著意义（P〉0．05）。两组在DPT组患儿应用谷氨酰胺双肽的第7、第14、第21天的天冬氨酸转氨酶（aspartate aminotransferase，AST），丙氨酸转氨酶（alanine aminotransferase，ALT），血尿素氮（blood urea nitrogen，BUN），肌酐（creatinine，Cr）、葡萄糖（glucose，Glu）、总蛋白（total protein，TP）、白蛋白（albumin，ALB）、球蛋白（globulin，GLB）、白细胞、红细胞（red blood cell，RBC）、血小板、血红蛋白（hemoglobin，Hb）比较，差异无显著意义（P〉0．05）。在应用谷氨酰胺双肽的第7、第14、第21天，DPT组患儿的体重下降幅度与对照组相应指标比较，下降幅度较少，差异有显著意义（P〈0．05）；且于第21天，DPT组患儿平均体重已恢复至造血干细胞移植前水平，而对照组尚未恢复。结论谷氨酰胺双肽对造血重建恢复无影响，但能改善造血干细胞移植患儿的营养状态，减少黏膜炎、肠炎的发生率及症状持续时间，减少长期发热发生率及发热持续时间，缩短抗生素治疗时间及无菌层流室治疗时间，同时不增加肠道急性移植物抗宿主疾病。

Effects of N(2)-L-alanyl-L-glutamine on Intestine in Children Underwent Hematopoietic Stem Cell Transplantation

Objective To investigate effects of N（2）- L - alanyl - L - glutamine（dipeptide grutamine;dipeptiven, DPT） on complications and recovery of pediatric patients with hematopoietic stem cell transplantation（HSCT）. Methods From March 2004 to November 2007, 56 pediatric patients with hematopoietic stem cell transplantation were assigned to receive either N （2）-L-alanyl-L-glutamine supplemented total parenteral nutrition （TPN） （DPT group, n= 28） or standard total parenteral nutrition （control group, n= 28） by means of stratified sampling of disease classification. The patients in DPT group received total parenteral nutrition enriched by 1.5 mL/（kg·d）N（2）-L-alanyl-L-glutamine injected for 21 days, and control group received glutamine-free total parenteral nutrition. Clinical chemistry index, blood cell count, body weight, complication and recovery of patients with hematopoietic stem cell transplantation were monitored and evaluated in all patients before and after total parenteral nutrition. Results 12 patients of DPT group and 26 patients of control group developed infantile diarrhea （P〈 0.05）. Duration of diarrhea, abdominal pain, vomiting and oral ulceration, frequencies of diarrhea, abdominal pain and vomiting were longer in control group than those of DPT group （P〈0. 05）. However, no significant difference was found in time length of oral candidiasis and anal fissure between two groups （P〉0.05）. Two patients of DPT group and ten cases of control group developed long term fever（≥14 days） （P〈0.05）. Time length of fever, frequencies of fever and the highest temperature were longer, much more and higher in control group than those of DPT group （P〈0.05）. There were 14, 4, 3 patients in DPT group and 19, 5, 1 patients in control group developed oral ulceration, oral candidiasis, anal fissure （P〉0.05）. There were no significant difference between two groups in bacterial and fungi culture positive patients （P〉0. 05）. Time length of antibiotic requirements and free-germ ward stay were shortened in DPT group （20.0± 7.1） dvs. （25.4±6.4） d, （20.2±6.7） d vs. （24.1±6.9） d;P〈0.05]. The time to reach 〉0.5×10^9/L neutrophils and the time to reach 〉20× 10^9/L platelets （PLT） were （ 15. 3 ± 5. 1 ） d, （29. 0 ± 14.4） d in DPT group and （16.2±5.8） d, （32.5 ±18.6） d in control group （P〉0.05）. There were 22 patients in DPT group and 21 patients in control group were successfully engrafted （P〉0. 05）. There were 3, 0 patients in DPT group and 5, 1 patients in control group developed acute intestinal graft versus host disease （aGVHD）, veno-occlusive disease （P〉0. 05）. No significant difference were found in clinical chemistry index and blood cell count between two groups （P〉0.05）. Loss of body weight in DPT group was less than that of control group after hematopoietic stem cell transplantation （P〈0.05）. Conclusion There is no difference in the time to neutrophil engraftment between two groups. Pediatric patients with hematopoietic stem cell transplantation will benefit from N （2）-L-alanyl-L-glutamine-supplemented total parenteral nutrition for the nutritional status improving, diminishing the incidence of mucositis, infantile diarrhea and long term fever, reducing the time of fever, free-ward stay and antibiotic requirements, and the incidence of acute intestinal graft versus host disease not increased.