1、2015加拿大早产儿喂养指南Guidelines for Feeding Very Low BirthWeight Infants,Nutrients 2015, 7, 423-442,主要内容,1.达到全胃肠内喂养的时间2.非营养性喂养、营养性喂养3.乳品选择4.无创通气极低体重儿的喂养5.喂养耐受性的评估6.胃潴留、胃食管返流的诊治7.母乳强化剂,Contents,1.Time to Reach Full Feeds2.Trophic Feeds、Nutritional Feeds3.Type of Milk for Starting Feeds4.Feeding Babies on No
2、n-Invasive Ventilation5.Assessment of Feed Tolerance6.Management of Residuals、Gastro-Esophageal Reflux (GER)7.Human Milk Fortification,引言,极低体重儿喂养的首要目标是在最短时间内达到全肠内营养，维持最好的生长和营养状态，并避免喂养速度过快导致的不良并发症。,Introduction,Adequate nutrition is essential for the optimal growth and health of very low birth weight
3、 (VLBW) infants. Enteral nutrition is preferred to total parenteral nutrition (TPN) because the former avoids complications related to vascular catheterization, sepsis, adverse effects of TPN, and fasting.,按照循证医学中心的标准标注出了证据级别（LOE），证据级别分类如下：,1a 随机对照研究（RCT）的系统评价1b 置信区间较窄的单个随机对照研究2a 队列研究的系统评价2b 单个的队列研究
4、或低质量的随机对照研究3a 病例对照研究的系统评价3b 单个的病例对照研究4 病例系列报道，低质量的队列研究或病例对照研究5 专家意见,Wherever possible, we have stated the level of evidence (LOE) as per the Centre for Evidence-based Medicine, United Kingdom . The outline of the LOE for therapy trials is as follows:,1a Systematic review (with homogeneity) of random
5、ized controlled trials (RCT)1b Individual RCT with narrow confidence interval (CI)2a Systematic review (with homogeneity) of cohort studies2b Individual cohort studies and low-quality RCTs3a Systematic review (with homogeneity) of case-control studies3b Individual case-control studies4 Case series,
6、poor-quality cohort and poor-quality case-control studies5 Expert opinion without explicit critical appraisal,达到全胃肠内喂养的时间,建议：出生体重1000g的早产儿喂养目标是生后2周内达到全胃肠内喂养（150-180ml/kg/d），1000-1500g早产儿目标是生后1周内达到全胃肠内喂养。个别早产儿特别是1000g以下早产儿不能耐受大量肠内喂养，因此本目标需要个体化评估。依据较快达到全胃肠内喂养可以尽快拔除血管内置管、减少败血症发生、减少其他导管相关的并发症（LOE 2b）。标准
7、化喂养方案可以改善极低出生体重儿预后。生后1周内达到全胃肠内喂养是完全可以做到的，在一项随机对照研究中，喂养量达到170ml/kg/d的中位时间是生后7天，而且并不增加呼吸暂停、喂养不耐受的发生率。,Time to Reach Full FeedsSuggestionAim to reach full enteral feeding (150180 mL/kg/day) by about two weeks in babies weighing 1000 g at birth and by about one week in babies weighing 10001500 g by impl
8、ementing evidence-based feeding protocols. It may be noted that some babies, especially those less than 1000 grams, will not tolerate larger volumes of feedings (such as 180 mL/kg/day or more) and thus may need individualization.RationaleReaching full enteral feeding faster results in earlier remova
9、l of vascular catheters, and less sepsis and other catheter-related complications (LOE 2b). Standardized feeding protocols improve outcomes in VLBWI . Reaching full feeds within a week is achievablein an RCT on VLBWI, the median time to reach 170 mL/kg/day was 7 days after fast advancement of entera
10、l feeding, with no increase in apneas, feed interruptions, and intolerance.,喂奶频次,建议：建议1250g以上早产儿每3小时喂奶一次。1250g以下早产儿尚无足够证据决定选择每隔3小时喂奶还是每隔2小时喂奶。 依据：在一项随机对照研究中，92名出生体重1250 g. There is not enough evidence to choose between two-hourly versus three-hourly feeds for babies weighing 1250 g.RationaleIn an RC
11、T, 92 neonates weighing 1750 g were allocated to either three- or two-hourly feeds. The incidence of feed intolerance, apnea, hypoglycemia, and necrotizing enterocolitis (NEC) did not significantly differ, and nursing time spent on feeding was significantly less in the three-hourly group (LOE 2b).Tw
12、o retrospective studies on this issue were contradictory. In one that compared 2-h and 3-h enteral feeding in ELBW babies, the time to full enteral feeding, enteral morbidity, hospital stay, and growth parameters were similar in the two groups (LOE 4). In another, VLBWI (mean birth weight 1200 g) fe
13、d twice hourly reached full feeds faster, received less prolonged TPN, and were less likely to have feeds held, compared to those fed three times hourly (LOE 4).,非营养性喂养：开始时间、喂养量、持续时间,建议：非营养性喂养定义为最小喂养量（10-15ml/kg/d）。建议生后24小时内开始非营养性喂养，超早产儿、超低出生体重儿及生长发育受限早产儿可适当谨慎处理。若生后24-48小时仍无母乳或捐赠母乳，可考虑代乳品喂养。尚无足够证据对营
14、养性喂养前的非营养性喂养持续时间做出建议。依据一项囊括了9项研究、754名极低出生体重儿的系统性综述中，非营养性喂养量为10-25ml/kg/d不等，开始喂养时间从生后一天开始。与禁食相比，尽早开始非营养性喂养并不能更早地达到全胃肠内喂养，NEC发生率无差异（LOE 1a-），需要进行更多研究以找到适合于极早产儿、超低出生体重儿和生长发育受限早产儿的临床建议。另一项系统性评价对开始营养性喂养的时间与预防NEC的关系进行综述，认为早期进行肠胃内喂养（生后1-2天）并不增加NEC、喂养不耐受的风险和死亡率（LOE 1a）。,Trophic Feeds: Time of Starting, Volu
15、me, DurationSuggestion：Trophic feeds are defined as minimal volumes of milk feeds (1015 mL/kg/day). Start trophic feeds preferably within 24 h of life. Exercise caution in extremely preterm, extremely low birth weight (ELBW), or growth-restricted infants. If, by 2448 h, no maternal or donor milk is
16、available, consider formula milk. There is not enough evidence to recommend the maximum duration of trophic feeding before starting nutritional feeds.Rationale：In a systematic review (nine trials, 754 VLBWI), the actual volume of trophic feeds ranged from 10 to 25 mL/kg/day; and onset from day one o
17、f life onwards. Early introduction of trophic feeds compared to fasting had a non-significant trend towards reaching full feeds earlier (mean difference 1.05 days (95% CI 2.61, 0.51) and no difference in NEC (LOE 1a). More data is required before one can generalize these findings to extremely preter
18、m, ELBW, or growth-restricted infants.In a systematic review (seven trials, 964 VLBWI) on timing of introduction of nutritional enteral feeding to prevent NEC, early introduction of progressive enteral feeding (1 to 2 days of age) did not increase the risk of NEC (typical relative risk (RR) 0.92 (95
19、% CI 0.64, 1.34), mortality (typical RR 1.26 (95% CI 0.78, 2.01), or feed intolerance (LOE 1a).,非营养性喂养的禁忌症,建议肠梗阻或会出现肠梗阻的情况时停止喂养。窒息、呼吸窘迫、败血症、低血压、血糖代谢紊乱、机械通气、脐血管置管不是非营养性喂养的禁忌症。依据一项荟萃分析指出伴有窒息、呼吸窘迫、败血症、低血压、糖代谢紊乱、机械通气、脐血管置管的极低出生体重儿未发现不良反应增加（LOE 1a-）。,Contraindications for Trophic Feeds SuggestionWithhold
20、 trophic feeds in intestinal obstruction or a setting for intestinal obstruction or ileus.Asphyxia, respiratory distress, sepsis, hypotension, glucose disturbances, ventilation, and umbilical lines are not contraindications for trophic feeds. RationaleThe studies included in a Cochrane review includ
21、ed VLBWI with asphyxia, respiratory distress, sepsis, hypotension, glucose disturbances, ventilation, and umbilical lines, without any excess adverse effects being reported (LOE 1a) .,营养性喂养：开始时机、喂养量、频次、增加速度,建议：出生体重1000g早产儿自30ml/kg/d开始营养性喂养，每天加奶30ml/kg/d。 依据：荟萃分析结果发现，快速加奶（30-35ml/kg/d）并不比慢速加奶（15-20ml
22、/kg/d）增加NEC风险、喂养中断和死亡率（LOE 1a），并且可以帮助早产儿更快恢复出生体重（LOE 1b）、更快达到全胃肠内喂养（LOE 2b）。暂时没有关于超低出生体重儿亚组的研究，我们建议超低出生体重儿从较小量开始喂养（15-20ml/kg/d）。,Nutritional Feeds: Day of Starting, Volume, Frequency, IncreaseSuggestionIn babies weighing 1 kg at birth, start nutritional feeds at 1520 mL/kg/day and increase by 1520
23、mL/kg/day. If the feeds are tolerated for around 23 days, consider increasing faster. For babies weighing 1 kg at birth, start nutritional feeds at 30 mL/kg/day and increase by 30 mL/kg/day.RationaleA Cochrane review individually reported that the fast daily increment group regained birth weight and
24、 reached full feeds faster (LOE 1b and 2b). As there was no subgroup analysis of ELBW babies, we suggest starting with a lower feed volume in ELBW babiesas in the control arm (1520 mL/kg/day)until more studies are available.,开始喂养时乳品选择,建议：首选母亲挤出的母乳或初乳，次选捐赠母乳，若均无可选早产儿专用奶粉。依据：新鲜挤出的母乳对早产儿有诸多益处。虽然没有对比新鲜母
25、乳和冷冻母乳的直接证据，但考虑到冷冻过程中共生物、免疫细胞、免疫因子消耗和酶活性下降，推荐使用新鲜母乳。母乳喂养（母亲母乳或捐赠母乳加母乳来源的增强剂）的新生儿比早产儿奶粉喂养或人乳加牛乳来源增强剂喂养组NEC发病率更低（LOE 1b）。一项成本效益分析研究表明，纯人乳品喂养降低NEC发病率，从而可以缩短住院时间，节省医疗费用（平均每个极早产儿节省8167美元）。,Type of Milk for Starting FeedsSuggestionThe first choice is own mothers expressed breast milk or colostrum. Second
26、choice: donor human milk.Third choice: preterm formula.RationaleFreshly expressed human milk has numerous benefits for preterm babies. Although there is no direct evidence comparing fresh versus frozen mothers milk, the use of fresh milk makes sense because of the depletion of commensals, immune cel
27、ls, immune factors, and enzyme activity that occurs with freezing. Neonates who receive an exclusively human milk-based diet (mothers milk or donor human milk with human milk-based fortifier) have significantly lower rates of NEC compared to those who receive preterm formula or human milk with a bov
28、ine milk-based fortifier (LOE 1b). however, a cost-effectiveness analysis showed that use of exclusively human milk-based products resulted in shorter duration of hospitalization (less by an average of 3.9 days in neonatal intensive care unit (NICU) and savings of $8167 per extremely premature infan
29、t (p 0.0001) because of the reduction in NEC.,伴不伴脐动脉舒张末期无血流或反流的小于胎龄儿（SGA）的喂养,建议：如果腹部查体未见异常，可以生后24小时内开始喂养，但加奶时谨慎，采取每日加奶量的最低值。29周小于胎龄儿伴脐动脉舒张末期无血流或反流者，生后10天内极其缓慢加奶。尽最大努力选择母乳，特别是脐动脉舒张末期无血流或反流、29周的小于胎龄儿。依据：Mihatsch等研究124例极低出生体重儿（其中35例伴有宫内生长发育受限），宫内生长发育受限组与无生长发育受限组达到全量喂养的时间无显著性差异。多元回归分析表明，脐动脉阻力、脑保护反射、Apga
30、r评分、脐动脉血pH、宫内生长发育受限等对达到全量喂养的时间无预测作用。一项关于产前脐血流异常的SGA早产儿的RCT研究中，早期喂养组和延迟喂养组NEC和喂养不耐受发生率无显著性差异（LOE 2b）。,Feeding Small for Gestational Age (SGA) Babies with/without History of Absent/Reversed End Diastolic Umbilical Flow (AREDF)SuggestionIf the abdominal examination is normal, start feeding within 24 h
31、of life, but advance slowly with volumes at the lowest end of the range. Advance feeds extremely slowly in the first 10 days among preterm SGA babies with gestation 29 weeks and AREDF. Make every effort to feed human milk, especially in SGA babies with AREDF and gestation 29 weeks.RationaleMihatsch
32、et al. fed 124 VLBWI (35 had intra-uterine growth retardation (IUGR) with a standardized protocol (LOE 2b). There was no statistical difference in the age to reach full feeds in the IUGR and non-IUGR groups (p = 0.6). In a multiple regression model, increased umbilical artery resistance, brain spari
33、ng, Apgar scores, umbilical artery pH, and IUGR did not predict the age to reach full feeds. In an RCT on SGA preterm babies (gestation of 2734 weeks) who had abnormal antenatal umbilical Doppler flows, the incidence of NEC and feeding intolerance was not significantly different (p = 0.35 and p = 0.
34、53, respectively) between the early feeders (n = 42; median age 2 days) and delayed feeders (n = 42; 7 days) (LOE 2b).,依据：另一项SGA早产儿的RCT研究对比了微量胃肠内喂养和禁食五天，NEC发病率无显著性差异，而且微量胃肠内喂养组有缩短NICU住院时间的倾向（LOE 2b）。一项名为“ADEPT”的RCT研究中，伴有脐动脉舒张末期无血流或反流和脑血流重新分布的402例SGA早产儿分为早期肠内喂养组（第2天）和晚期肠内喂养组（第6天），早期肠内喂养组更早达到全量喂养，NEC总
35、发病率和II-III期NEC发病率均无显著性差异，早期喂养组全肠外营养时间短，重症监护时间短，胆汁淤积症发生率低（LOE 1b）。,In an RCT on preterm SGA infants, comparing minimal enteral feeding and no enteral feeding for five days, there was no difference in the rate of NEC (p = 0.76) and there was a trend towards shorter NICU stay in the enteral feeding gro
36、up (p = 0.2) (LOE 2b).In the Abnormal Doppler Enteral Prescription Trial (ADEPT) RCT, 402 preterm SGA infants (35 weeks gestation, birth weight 10th centile) with absent or reversed end diastolic umbilical blood flow and cerebral redistribution were allocated to early or late onset of enteral feedin
37、g (Day 2 or 6, respectively) (LOE 1b).The early feeding group reached full enteral feeds faster than the late feeding group (median (IQR) days: 18 (1524) versus 21 (1927), respectively; p = 0.003). There was no difference in the incidence of all-stage NEC (18% versus 15%, respectively; p = 0.42) and stage IIIII NEC.,无创通气极低体重儿的喂养,建议谨慎加奶。不能把腹胀作为喂养不耐受的征象，在1000g早产儿尤其如此。依据无创通气可以导致腹胀，经鼻持续气道正压通气（nCPAP）降低早产儿的餐前餐后肠血流量（LOE 4）。Jaile等人的研究对比25例nCPAP早产儿和29例无CPAP的早产儿，1000g和1000g早产儿中分别有83%和14%因CPAP导致肠胀气，本研究中无NEC病例，但本研究样本量太小不能对NEC发病率做出结论。,
