WO2020051817A1 - 一种用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉及其使用方法 - Google Patents

一种用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉及其使用方法 Download PDF

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WO2020051817A1
WO2020051817A1 PCT/CN2018/105382 CN2018105382W WO2020051817A1 WO 2020051817 A1 WO2020051817 A1 WO 2020051817A1 CN 2018105382 W CN2018105382 W CN 2018105382W WO 2020051817 A1 WO2020051817 A1 WO 2020051817A1
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surgery
infants
protein
energy
congenital heart
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PCT/CN2018/105382
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English (en)
French (fr)
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马则铭
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北京诺爱真原生物科技有限公司
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Priority to CN201880003526.1A priority Critical patent/CN109714975A/zh
Priority to AU2018417113A priority patent/AU2018417113A1/en
Priority to EP18887208.9A priority patent/EP3643179A1/en
Priority to US16/469,645 priority patent/US20210106626A1/en
Priority to PCT/CN2018/105382 priority patent/WO2020051817A1/zh
Publication of WO2020051817A1 publication Critical patent/WO2020051817A1/zh
Priority to AU2021200676A priority patent/AU2021200676A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/16—Agglomerating or granulating milk powder; Making instant milk powder; Products obtained thereby
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/20—Dietetic milk products not covered by groups A23C9/12 - A23C9/18
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to foods for special medical purposes, in particular to a nutritional infant formula for congenital heart surgery and non-cardiac surgery and other critically ill infants.
  • the milk powder on the market belongs to the "formula milk powder" formulated by scientific and technological methods, that is, milk is used as raw materials, and some materials are added or extracted.
  • Nutricia milk powder products Take Nutricia milk powder products as an example. Nutricia is one of the world's largest children's milk powder brands. It belongs to the French Danone Group and is headquartered in the Netherlands. Nutrilon's market share of Nutrilon milk powder designed for healthy infants exceeds 70%. Healthy infant milk powder includes Nounone 1st stage (0-6 month infant) and 2nd stage (6-12 month infant) milk powder, whose energy to protein ratio is 65kcal: 1.4g and 69kcal: 2.2g / 100ml standard powder Transfer liquid.
  • the energy of Nuoyou is slightly higher, and the protein is seriously insufficient; the energy of Newquan is much higher than required, and The amount of protein is still insufficient.
  • Another example is the special preNan milk powder designed by Nestle in Switzerland for premature and low birth weight infants.
  • the energy to protein ratio is 82kcal: 2.3g / 100ml, which is higher than the critical baby's requirement, while the amount of protein is still insufficient.
  • composition of known milk formulas such as Infatrini high-energy fortified infant formula is as follows:
  • Vitamin B1 ug 150
  • Vitamin B2 ug 150
  • Niacin ug 1200
  • Pantothenic acid ug 500
  • Vitamin B6 ug 60
  • Folic acid ug 15
  • Vitamin B12 ug 0.41
  • Biotin ug 2.3
  • Vitamin C ug 13
  • Sodium mg 42 Potassium: mg 100
  • Calcium mg 101
  • Phosphorus mg 57
  • Magnesium mg 7.5 Iron: mg 1 Zinc: mg 0.9
  • the invention thus provides a nutritional infant formula for congenital heart surgery and non-cardiac surgery and other severe infants.
  • the energy-to-protein ratio of the formula is 55-60 kcal: 3-4.0 g / 100 ml.
  • the energy-to-protein ratio is: 55 kcal: 4 g / 100 ml.
  • it is used for extracorporeal circulation of infants and non-cardiac surgery and other severe infants.
  • it is used for infants on extracorporeal circulation to start feeding after 6 hours. Begin feeding within 24 hours of non-cardiac surgery and other critically ill infants admitted to the hospital.
  • it is used within 5 days after the baby's extracorporeal circulation. 7-14 days after non-cardiac surgery and other severe infants staying in the intensive care unit.
  • the infant is 0-2 years old.
  • the infant is 0-12 months.
  • the infant is under 12 months.
  • the present invention also proposes a feeding method using the aforementioned infant formula for congenital heart surgery and non-cardiac surgery and other intensive care nutrition infant formulas, and advocacy feeding is performed 6 hours after the operation. Start within 24 hours of non-cardiac surgery and other critically ill infants admitted to hospital.
  • the method of assessing protein requirements is to measure daily nitrogen balance.
  • the nitrogen balance method needs to accurately quantify the daily nitrogen intake and nitrogen loss, and accurately calculate the balance between the two.
  • few centers actually measure resting energy expenditure and nitrogen balance. It is more to estimate the energy demand with calculation formulas derived from healthy children. These formulas do not apply to critically ill children, which has been known for 20 years.
  • the protein and energy feeding program for children in the integrated pediatric intensive care unit is based on the results of comprehensive international studies reviewing nearly 20 years, and the protein and energy feeding program for babies after congenital heart disease is based on the first international direct and indirect Calorimetry measures daily resting energy expenditure to guide energy feeding, while measuring the daily nitrogen balance of different levels of protein intake groups.
  • the metabolic characteristics and literature data of the two groups of children were compared, and a new scheme for protein and energy feeding was finally obtained.
  • the protein intake of children is very different, generally low, most of which are 0-2g / kg / d, a few reach 3g / kg / d, and very few reach 4g / kg / d.
  • a minimum protein intake of 1.5 g / kg / d can reach zero nitrogen balance and an energy intake of 58 kcal / kg / d.
  • the 2018 Critical Care Medicine and American Society of Parenteral and Enteral Nutrition's Pediatric Critical Patient Nutrition Guidelines clearly state that protein intake above this threshold can prevent cumulative negative protein balance and improve prognosis.
  • the optimal protein intake required to achieve positive nitrogen balance may be well above this minimum threshold.
  • Table 1 which records the clinical effects of the innovations of the present invention.
  • Isotope labeling is the most accurate and detailed method for measuring all aspects of protein metabolism (including synthesis, decomposition, and turnover), but the technology is more difficult and rarely used centrally.
  • Dr. Paul Pencharz a world-renowned expert in protein metabolism for children, the net protein synthesis rate of infants with high protein intake (3.9g / kg / day) compared with low-protein group (2.3g / kg / day) after non-cardiac surgery (Ie synthesis minus decomposition) increased significantly. This improvement in nitrogen utilization is primarily achieved by reducing endogenous proteolysis.
  • the protein requirement of infants in the integrated pediatric intensive care unit is 3-4g / kg / day, and the energy requirement is 55-60kcal / kg / day.
  • enteral nutrition is still the preferred way of nutrition supply.
  • early intestinal nutrition 25-100% of the expected value within 24-48 hours
  • enteral nutrition guidelines for pediatric critically ill patients recommend that early feeding and then gradual increase are appropriate methods for enteral feeding.
  • This patent-pending new technology is based on the scientific data of the world's first trial to simultaneously measure resting energy expenditure and nitrogen balance, and to derive the energy and protein requirements of infants with congenital heart disease in the early postoperative period, that is, 55kcal / kg / day and 4g / kcal / day, and the ratio of the two, that is, 55kcal: 4g / 100ml.
  • this trial measured the resting energy expenditure of 40 children with complex congenital heart disease every day for 5 days after surgery and gave energy accordingly.
  • these children were randomly divided into 3 groups, each group was given different doses of protein, respectively the control group (conventional treatment group, protein intake 1.3g / kg / day), medium protein group (2.5g / kg / day) , High protein group (4g / kg / day), nitrogen balance was measured daily.
  • the protein supply that reaches the earliest positive nitrogen balance is the protein requirement.
  • All nutritional regimens are supplied by enteral feeding, which begins 6 hours after surgery and lasts 5 days. The results are shown in Table 2.
  • Formulated milk based on this scientific data will likely improve early recovery from congenital heart surgery and non-cardiac surgery and other critically ill infants.
  • Even there is no interventional clinical study of reasonable energy protein nutrition program for recovery of children after cardiopulmonary bypass surgery in infants with congenital heart disease observational studies have repeatedly confirmed that malnutrition affects the rehabilitation of critically ill children.
  • the average daily energy and protein supply targets are 64kcal / kg and 1.7g / kg, respectively, but the actual average intake is only 38% of the target energy and 43% of the target protein.
  • Protein, carbohydrates and fats are the three major nutrients that provide energy. Among them, the energy of protein and carbohydrate is 4kcal / g, and the fat is 9kcal / g.
  • formula milk powder based on the known formula milk formula, or based on the proportion arrangement of the present invention on the basis of the existing formula milk powder. For example: milk powder ratio: per 100ml, energy 55kcal, protein 4g, carbohydrate 5g, fat 2.3g.

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Abstract

一种用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉,其特征在于，该奶粉的能量与蛋白质比为：55-60kcal：3-4.0g/100ml。

Description

一种用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉及其使用方法 技术领域
本发明涉及特殊医学用途食品，特别是一种用于先天性心脏病手术和非心脏手术后和其他重症婴儿监护营养婴儿配方奶粉。
背景技术
目前市场上的奶粉都属于以科技方法调配的“配方奶粉”，即以牛奶为原料，另外再加入或抽取出某些物料而制成。
先天性心脏病患儿大多于婴儿期内行体外循环开心手术治疗。这些小婴儿手术前大多营养状态低下，能量和蛋白储备不足。其他手术和重症监护室儿童，入院时也有很多营养状态低下。手术后和病情危重在监护室期间，患儿受全身炎症反应等因素的影响，分解代谢增强合成代谢减弱，营养供给不足加重营养不良。术后合理的营养喂养是影响恢复的重要因素。营养成分中最重要的就是能量和蛋白的适量供给，包括二者的绝对量和配比。但是，由于复杂的代谢改变，合理的能量和蛋白营养方案的设计比较复杂。目前的营养喂养的方案几乎没有科学依据，即使在2018年发表的最权威的美国肠外肠内营养学会和危重病医学学会儿科重症监护的营养支持临床指南中，仍承认数据不足，小儿心脏手术后的数据很少。目前世界上有多款适用于健康婴儿奶粉配方，也有少数特殊医学用途配方，适用于乳糖不耐受，蛋白过敏、胃肠道先天性代谢异常的婴儿等，还有低出生体重婴儿的高能 量高蛋白配方。但先天性心脏病术后和其他危重症婴儿所需奶粉配方仍是空白，其特点是能量需要量减低，而蛋白需要量增高。
目前儿童世界上所有奶粉配方中，大多数为健康婴儿喂养奶粉，能量和蛋白的比例均不适用于先天性心脏病手术和非心脏手术后和其他重症婴儿。以纽迪希亚(NUTRICIA)奶粉产品为例。纽迪希亚是全球最大儿童奶粉品牌之一，隶属于法国达能集团(DANONE)，总部位于荷兰。纽迪西亚为健康婴幼儿设计的诺优能(Nutrilon)奶粉市场占有率超过70％。健康婴儿奶粉包括诺优能1段(0-6个月婴儿)和2段(6-12个月婴儿)奶粉，其能量与蛋白比例分别为65kcal：1.4g和69kcal:2.2g/100ml标准冲调液。该公司为低体重或重症婴儿设计的一款奶粉，纽荃星(Infatrini)高能量强化营养婴儿配方粉，其能量与蛋白比为100kcal：2.6g/100ml，该产品已被推荐和运用于先天性心脏病手术和非心脏手术后和其他重症儿童，但仍为研究阶段。但对先天性心脏病和其他危重症婴儿来说，虽然大多患儿肠内喂养能够耐受，诺优能的能量略高，而蛋白严重不足；纽荃星的能量远高于需要量，而蛋白量仍不足。再如瑞士雀巢公司(Nestle)为早产儿及低出生体重儿设计的特别能恩(preNan)奶粉,能量与蛋白比为82kcal：2.3g/100ml,能量高于危重婴儿需要量，而蛋白量还是不足。
已知的奶粉配方比如纽荃星(Infatrini)高能量强化营养婴儿配方粉组成如下：
项目：单位 /100ml标准
能量:kcal 100
蛋白:g 2.6
碳水化物:g 9.9
脂肪:g 5.4
膳食纤维：g 0.6
维生素A：ug RE 83
维生素D: 2
维生素E:mg a-TE 1.1
维生素K1:ug 5.9
维生素B1:ug 150
维生素B2:ug 150
烟酸:ug 1200
泛酸:ug 500
维生素B6:ug 60
叶酸:ug 15
维生素B12:ug 0.41
生物素:ug 2.3
维生素C:ug 13
钠：mg 42
钾：mg 100
氯：mg 62
钙：mg 101
磷：mg 57
镁：mg 7.5
铁：mg 1
锌：mg 0.9
铜：mg 60
锰:ug 50
硒:ug 2.5
碘:ug 16
胆碱:ug 14
肌醇：mg 25
牛磺酸：mg 6.9
核苷酸：mg 4.3
发明内容
根据世界文献检索有关重症患儿营养研究，得出综合儿童监护室婴儿(包括非心脏手术、创伤、败血症等)能量和蛋白和蛋白需最佳需要量和配比。
根据直接测量的能量和蛋白实际需要量的科学数据，得出先天性心脏病婴儿手术后所需的能量和蛋白的配比。
两组患儿的能量和蛋白代谢特征相似，能量和蛋白需要也相似量，即低能量高蛋白。
本发明从而给出了一种用于先天性心脏病手术和非心脏手术后及其他重症婴儿营养婴儿配方奶粉，该奶粉的能量与蛋白质比为：55-60kcal：3-4.0g/100ml。
最好，所述能量与蛋白质比为：55kcal：4g/100ml。
优选地，用于婴儿体外循环述后和非心脏手术后及其他重症婴儿。
最好，用于婴儿体外循环述后6-24个小时内开始喂养。非心脏手术后及其他重症婴儿入院后24小时内开始喂养。
优选地，用于婴儿体外循环述后6个小时后开始喂养。非心脏手术后及其他重症婴儿入院后24小时内开始喂养。
最好，用于婴儿体外循环述后5天内。非心脏手术后及其他重症婴儿入住监护室后的7-14天内。
优选地，所述婴儿为0-2岁。
最好，所述婴儿为0-12个月。
最好，所述婴儿为12个月以下。
本发明还提出一种使用上述的用于先天性心脏病手术和非心脏手术后和其他重症监护营养婴儿配方奶粉的喂养方法，在手术后6个小时后进行倡导喂养。在非心脏手术后及其他重症婴儿入院内24小时内开开始。
具体实施方式
先天性心脏病体外循环手术后患儿和其他儿科重症监护室患儿(包括非心脏手术后，创伤、败血症等等)的营养状况和代谢改变有很多共同特征，如入院前营养不良发生率可达30-50％。术后或病情危重期间，由于手术或疾病本身，更主要的是由于全身炎症反应，导致代谢紊乱，表现为蛋白质分解代谢增强、合成代谢减低。蛋白分解提供游离氨基酸，这些氨基酸被导向组织修复、伤口愈合和炎症反应。这种反应能造成危重患儿的肌肉重大损失。同时能量代谢和需要量也改变，炎症反应刺激代谢增加，但同时患儿生长受到抑制或停止，供生长部分的营养不应喂养。所以，制定适当能量和蛋白喂养方案甚为复杂。蛋白和能量严重供给不足进一步加重肌肉损失，加重不良结局， 而增加营养可降低不良结局的发生。重症患儿的适当蛋白质摄入量的目的是，在应激反应所造成的分解代谢的情况下维持蛋白质平衡。除了蛋白质摄入量，能量摄入量也会影响危重疾病中的蛋白质平衡。但是至今，尚无严谨设计的前瞻性研究同时测量危重患儿的能量和蛋白需要量。
根据世界卫生组织(WHO)建议，评估蛋白质需要量的方法是测量每日的氮平衡情况。氮平衡法需要精确定量每日氮元素摄入量及氮元素损失量，并准确计算两者收支平衡的情况。2018年危重病医学学会和美国肠外肠内营养学会发表的儿科危重病人营养支持供给和提供和评估指南建议，通过间接量热法测量静息能量消耗，用于确定能量需求并指导日常能量目标的处方。但是，由于理念和技术的限制，很少中心实际测量静息能量消耗和氮平衡。更多的是用根据健康儿童推算得出的计算公式估计能量需要量。而这些公式不适用于危重症患儿，这一点已经认识20年了。
虽然普遍认为这些危重患儿的营养代谢和利用与健康儿童不同，近10年来开始关注重症患儿的营养，但能量和蛋白质需要量的证据仍有限，能量和蛋白质的最佳供给量仍未知。相比先天性心脏病体外循环手术后，有关综合儿科重症监护室患儿的能量蛋白需要量的研究更多一些。
以下分两部分阐述两组患儿的临床特点和营养喂养的研究。关于综合儿科重症监护室患儿的蛋白和能量喂养方案是根据回顾近20年 的国际综合研究结果，而关于先天性心脏病术后婴儿的蛋白和能量喂养方案是根据国际第一个直接用间接量热法每天测量静息能量消耗指导能量喂养，同时测量不同等级蛋白摄入组的每日氮平衡。比较两组患儿的代谢特点和文献数据，最后得出适合两组患儿蛋白和能量喂养的新的方案。
一、综合儿科重症监护室患儿
综合儿科重症监护室的患儿，入院时营养不良的比率约为20-45％。在监护室期间，由于上述原因，营养不良加重。入院时和住院期间的营养不良严重影响患儿转归(包括呼吸机时间、监护室时间、住院时间、住院期间感染率和死亡率)。已有一些研究用间接量热法测量静息能量消耗，其平均范围为55-60kcal/kg/day。但是，由于技术困难，静息能量消耗的测量没有广泛开展。相比之下，蛋白质需要量研究更少。仅有少数试验检查重症监护患儿的氮平衡和能量摄入量(表1)。这些研究中高蛋白组的蛋白摄入量为2.8-3.1g/kg/day，并在入监护室5天内达到正氮平衡，能量需要量有些是根据公式估算得出的，有些没有考虑，而实际摄入量为22-112kcal/kg/day。至今，几无前瞻性研究同时测量危重患儿的能量和蛋白需要，并据实际需要给予营养。Chaparro等测量了静息能量消耗并指导能量喂养，并同时测量了氮平衡检查蛋白需要量。但是，该研究没有严格设计蛋白喂养方案，而是根据监护室期间临床喂养的纵向数据和回归分析得出的蛋白和能量需要量。患儿的蛋白摄入量非常不同，普遍低，大多为0-2g/kg/d，少数达到3g/kg/d，极少达4g/kg/d。其结论是，最低 蛋白质摄入1.5g/kg/d可以达到氮平衡为零，同时能量摄入58kcal/kg/d。然而，2018年发表的危重病医学学会和美国肠外肠内营养学会儿科危重病人营养指南中明确指出，蛋白摄入量高于这个阈值可以防止累积的负蛋白平衡，改善预后。在危重患儿，获得正氮平衡所需的最佳蛋白质摄入量可能远高于这个最小值阈值。
下表为表1，记录了本发明创新点的临床效果。
表1
Figure PCTCN2018105382-appb-000001
表1
Figure PCTCN2018105382-appb-000002
表1
Figure PCTCN2018105382-appb-000003
表1
Figure PCTCN2018105382-appb-000004
其中上表中相关信息为：估算的基础代谢率；EN，外部营养；HP，高蛋白；MOSF，多器官系统衰竭；RDA,推荐每日供给量；RSV，呼吸同步细菌；S，组标准，级别和评价通过使用来自2013年美国饮食协会证据分析手册而被确定的。所有值都是以平均值(SD)示出，除了另外注明的。
同位素标记法是最精准细致的测量蛋白代谢的各个环节(包括合成、分解和周转)的方法，但技术更难，极少中心使用。世界著名儿童蛋白代谢专家Paul Pencharz医生的研究显示，非心脏外科术后婴儿高蛋白摄入量(3.9g/kg/day)比较低蛋白组(2.3g/kg/day)组的净蛋白合成率(即合成减去分解)显著增高。这一氮利用的改善的主要通过减少内源性蛋白分解来实现的。
综上所述，综合儿科重症监护室婴儿的蛋白需要量为3-4g/kg/day，能量需要量为55-60kcal/kg/day.
另外，目前已达成共识，肠内营养仍是营养供给的首选途径。2018年发表的研究结果显示，早期(24-48小时达到预期值的25-100％)开始肠内营养显著减低死亡率和住院费用。最新的危重病医学学会和美国肠外肠内营养学会儿科危重病人营养指南建议早期喂养，然后逐步增加是肠内喂养的合适方法。
二、先天性心脏病体外循环手术后患儿
先天性心脏病发病率在世界范围内为6-10‰，大多在婴儿期内行体外循环手术。
先天性心脏病患儿的营养不良问题更加严重。先天性心脏病患儿术前消化系统微循环缺血缺氧导致营养摄入不足和吸收不良，并且长期存在的高代谢状态导致患儿能量储备不足。1岁以下患儿中、重度营养失衡的发生率可高达50％，是最常见的合并症之一。术后，体外循环导致的全身炎症反应使分解代谢增强而合成代谢减弱，加上常规使用的血管活性药物刺激能量消耗，使静息能量消耗和蛋白分解显著增加。另一方面，目前的临床治疗方案仍是限制液体入量和营养供给，导致了术后早期极差的营养状态。已知仅有5项研究涉及了能量比较量，即需要量和供给量。该研究表明：术后24小时内，能量供给仅为所需的7-20％。
蛋白质需要量的研究数据更少。美国肠内外营养协会提供的指南建议重症儿童蛋白质每日的摄入量按年龄分别为0-2岁，2-3g/kg，但同时也承认缺少充足的数据支持，特别是在体外循环术后的患儿。目前，仅有3篇文献对先心病患儿术后早期的蛋白质需求量进行了评估，但均因试验设计问题未得出肯定结论。
在危重病人的营养方案上，目前共识是肠内喂养优于肠外营养，而且尽早满足营养需求，但实际实施在各中心之间差别很大。在欧洲，约30％的儿童心脏监护室于术后12-24小时内开始肠内喂养，72％术 后1-3天内开始中心静脉肠外营养。然而，越来越多的证据支持术后尽早(6小时)开始肠内喂养奶粉是安全有效的。
综上所述，在先心病治疗技术高速发展，各种术后营养治疗指南强烈推荐合理营养治疗的大环境下，由于技术难度和观念落后，术后早期营养喂养二十年来一直止步不前，有关能量、蛋白的需要量和喂养途径仍未知。
这项申请专利的新技术是根据世界第一个试验同时测量的静息能量消耗和氮平衡的科学数据，得出婴儿先心病术后早期的能量和蛋白需要量，即55kcal/kg/day和4g/kcal/day,和二者的配比,即55kcal：4g/100ml。
具体来说，这项试验是在40名复杂先天性心脏病患儿术后5天内，每天测量静息能量消耗，并据此给予能量。同时，这些患儿随机分为3组，每组给予不同剂量的蛋白，分别为对照组(常规治疗组，蛋白摄入1.3g/kg/day)，中蛋白组(2.5g/kg/day)，高蛋白组(4g/kg/day)，每天测量氮平衡。最早达到正氮平衡的蛋白质供给量即为蛋白需要量。所有的营养方案的供给是通过肠道喂养，在术后6小时开始，并持续5天。结果见表2.数据显示，高蛋白组术后当天即达到正氮平衡，术后第1天有所下降，为负氮平衡，术后2至4天又成为正氮平衡。而其余两组5天内均为负氮平衡。而且患儿可以耐受通过肠道喂养。这些均是世界首次发现。
表2.婴儿体外循环术后5天内3个不同蛋白摄入量组的静息能量消耗、能量摄入和氮平衡的比较
Figure PCTCN2018105382-appb-000005
其中：婴儿年龄：20天-600天，能量蛋白质比的下限值：50：3。能量蛋白质比中间值：55:4(最佳值)，能量蛋白质比上限值：60:4，n为病人数。
结果：如表2所示，在5天的试验期间，3组之间静息能量消耗和能量摄入量无明显差异(P值无统计学差异，NS)。3组氮平衡逐渐增加(Ptime<0.0001)，且随蛋白摄入增高，氮平衡在5天内增高显著(Pgroup*time<0.0001)。高蛋白组术后当天即达到正氮平衡，术后第一天因尿量增多而为负氮平衡，之后三天均为正氮平衡。而其他两组所有时间内均为负氮平衡(Pgroup<0.0001)
结论：4g/kg/day为蛋白需要量。能量需要量在术后当天较高65kcal/kg/d，但仅能喂入约40kcal/kg/d(达需要量的62％，远高于之前报道的7‐20％)。其它4天内，平均能量需要为55kcal/kg/d，且与摄入平衡。
所以，对先天性心脏病术后婴儿奶粉能量：蛋白合理配方为本发明提出的方案。同时，根据上述在其他重症婴儿研究所发表的文献，这一奶粉能量：蛋白配方也适用于非心脏手术和其他重症婴儿。
根据这一科学数据配比的奶粉将很可能改善先天性心脏病手术和非心脏手术和其他重症婴儿的早期恢复。虽然目前尚无先天性心脏病婴儿体外循环手术后合理能量蛋白营养方案对患儿恢复的干预性临床研究，但已有观察性研究反复证实营养不良影响重症儿童康复。一项在8个国家中的31家重症儿童监护室的400名患儿的研究发现，30％患儿入院时有严重营养不良。平均每日能量和蛋白质供给量的目标分别为64kcal/kg和1.7g/kg，但是，实际平均摄入量仅为目标能量的38％，目标蛋白量43％。研究者进一步发现，通过肠内营养途径喂养的较高目标能量百分比与60天内低死亡率显著相关(增加能量摄入从33.3％到66.6％的优势比为0.27(0.11，0.67)，P＝0.002)。同一研究团队的另一项大型前瞻性队列研究发现，在15个国家中的59家重症儿童监护室的1245名患儿中，目标蛋白量为1.9g/kg/day，较高蛋白摄入的患儿(摄入量高于目标量60％)比低蛋白摄入的患儿(肠内营养途径蛋白摄入低于目标量20％)，60天内的死亡率显著减低(优势比为0.14(95％CI:0.04,0.52；P＝0.003)。需要指出 的是，以上两项研究有一定局限性，患儿年龄跨度大(1月至18岁)，而能量和蛋白需要量随年龄变化很大，所以单一的能量和蛋白目标摄入量不能达到合理喂养。另外，两个实验的患儿大多为幼儿和学龄儿,而且为非体外循环心脏手术患儿，所以目标蛋白喂养量较低。
蛋白、碳水化合物和脂肪为三大营养元素，提供能量。其中，蛋白、碳水化合物的能量为4kcal/g,脂肪为9kcal/g。本领域技术人员根据已知的奶粉配方，或者在现有奶粉的基础上可以基于本发明的比例安排获得相应的配方奶粉。比如：奶粉配比：每100ml,能量55kcal，蛋白4g,碳水化合物5g,脂肪2.3g。
所述实施例仅是本发明的优选实施方式，在本技术领域内，凡是基于本发明技术方案的变化和改进，不应排除在本发明的保护范围之外。

Claims (10)

  1. 一种用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉,其特征在于，该奶粉的能量与蛋白质比为：55-60kcal：3-4.0g/100ml。
  2. 根据权利要求1所述的用于先天性心脏病手术和非心脏手术后和其他重症监护营养婴儿配方奶粉，其特征在于，所述能量与蛋白质比为：55kcal：4g/100ml。
  3. 根据权利要求2所述的用于先天性心脏病手术后和非心脏手术和其他重症监护营养婴儿配方奶粉，其特征在于，用于婴儿体外循环手术和非心脏手术后以及重症监护期间。
  4. 根据权利要求3所述的用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉，其特征在于，用于婴儿体外循环述后6-24个小时后开始喂养；在非心脏手术后和其他重症婴儿，于24-48小时内开始喂养。
  5. 根据权利要求4所述的用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉，其特征在于，用于婴儿体外循环述后6个小时后开始喂养；在非心脏手术后和其他重症婴儿，于24小时内开始喂养。
  6. 根据权利要求5所述的用于先天性心脏病手术和非心脏手术后和其他重症监护婴儿营养配方奶粉，其特征在于，用于婴儿体外循环述后5天内；在非心脏手术后和其他重症婴儿，用于入住监护室后的7-14天内。
  7. 根据权利要求6所述的用于先天性心脏病手术和非心脏手术后和其他重症婴儿监护营养婴儿配方奶粉，其特征在于，所述婴儿为0-2岁。
  8. 根据权利要求7所述的用于先天性心脏病手术和非心脏手术后和其他重症婴儿监护营养婴儿配方奶粉，其特征在于，所述婴儿为0-12个月。
  9. 根据权利要求8所述的用于先天性心脏病手术和非心脏手术后和其他重症婴儿监护营养婴儿配方奶粉，其特征在于，所述婴儿为12个月以下。
  10. 一种使用根据权利要求1-9任一项所述的用于先天性心脏病手术和非心脏手术后和其他重症婴儿监护营养婴儿配方奶粉的喂养方法，其特征在于，在先天性心脏病手术后6个小时后进行倡导喂养；在非心脏手术后和其他重症婴儿，入住监护室后24小时内进行肠道喂养。
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