Abstract：
Critically ill children are fed day and night, assuming this improves enteral tolerance and the probability of achieving nutritional goals. It was previously shown that a fasting response, reflected by increased ketosis, at least partly explained the beneficial outcome of delayed initiation of supplemental parenteral nutrition. This study aims to investigate whether an overnight fast increases ketosis and is feasible and safe in critically ill children.
The Continuousversus Intermittent Nutrition in Paediatric Intensive Care (ContInNuPIC) study is a randomised controlled trial in a tertiary referral Paediatric Intensive Care Unit (PICU) in the Netherlands. Critically ill children (term newborn-18 years) with an expected PICU stay ≥48 h, dependent on artificial nutrition, were eligible. Participants were randomly assigned (1:1, stratified for age group) to intermittent feeding, with interruption of feedings during an age-dependent overnight period of eight to 12 h, or to continuous feeding, with the administration of feedings day and night. In both groups, similar daily caloric targets were pursued. For children younger than one year, mandatory minor glucose infusions were provided during fasting. The primary outcome was the feasibility, defined as two conditions (1): a significant difference in the patients\' highest daily ketone (3-β-hydroxybutyrate, BHB) levels during each overnight period, and (2): non-inferiority regarding daily caloric intake, examined using a two-part mixed-effects model with a predefined non-inferiority margin of 33%, in an intention-to-treat analysis. The study is registered in the Netherlands Trial Register (NL7877).
Between May 19, 2020, and July 13, 2022, 140 critically ill children, median (first quartile; third quartile) age 0.3 (0.1; 2.7) years, were randomised to intermittent (n = 67) or continuous feeding (n = 73). In the intermittent feeding group, BHB levels were significantly higher (median 0.4 (0.2; 1.0) vs. 0.3 (0.1; 0.7) mmol/L, p < 0.001). The ratio of total caloric intake in the intermittent feeding group to the intake in the continuous feeding group was not consistently significantly more than 0.67, thus not proving non-inferiority. No severe, resistant hypoglycaemic events, nor severe gastrointestinal complications related to the intervention occurred, and feeding intolerance did not occur more often in the intermittent than in the continuous feeding group.
Compared with day and night feeding, intermittent feeding with an overnight fast and mandatory glucose infusion for children younger than one year marginally increased ketosis and did not lead to more hypoglycaemic incidents in critically ill children. Because non-inferiority regarding daily caloric intake was not proven, the feasibility of an overnight fast could not be shown in the current study. However, as feeding intolerance did not increase during the condensed feeding periods, the nutritional intake was probably limited by the prescription of nutrition and interruptions. More research is needed to determine the optimal level and duration of clinically relevant ketosis and the best method to achieve this.
The Continuousversus Intermittent Nutrition in Paediatric Intensive Care (ContInNuPIC) study is a randomised controlled trial in a tertiary referral Paediatric Intensive Care Unit (PICU) in the Netherlands. Critically ill children (term newborn-18 years) with an expected PICU stay ≥48 h, dependent on artificial nutrition, were eligible. Participants were randomly assigned (1:1, stratified for age group) to intermittent feeding, with interruption of feedings during an age-dependent overnight period of eight to 12 h, or to continuous feeding, with the administration of feedings day and night. In both groups, similar daily caloric targets were pursued. For children younger than one year, mandatory minor glucose infusions were provided during fasting. The primary outcome was the feasibility, defined as two conditions (1): a significant difference in the patients\' highest daily ketone (3-β-hydroxybutyrate, BHB) levels during each overnight period, and (2): non-inferiority regarding daily caloric intake, examined using a two-part mixed-effects model with a predefined non-inferiority margin of 33%, in an intention-to-treat analysis. The study is registered in the Netherlands Trial Register (NL7877).
Between May 19, 2020, and July 13, 2022, 140 critically ill children, median (first quartile; third quartile) age 0.3 (0.1; 2.7) years, were randomised to intermittent (n = 67) or continuous feeding (n = 73). In the intermittent feeding group, BHB levels were significantly higher (median 0.4 (0.2; 1.0) vs. 0.3 (0.1; 0.7) mmol/L, p < 0.001). The ratio of total caloric intake in the intermittent feeding group to the intake in the continuous feeding group was not consistently significantly more than 0.67, thus not proving non-inferiority. No severe, resistant hypoglycaemic events, nor severe gastrointestinal complications related to the intervention occurred, and feeding intolerance did not occur more often in the intermittent than in the continuous feeding group.
Compared with day and night feeding, intermittent feeding with an overnight fast and mandatory glucose infusion for children younger than one year marginally increased ketosis and did not lead to more hypoglycaemic incidents in critically ill children. Because non-inferiority regarding daily caloric intake was not proven, the feasibility of an overnight fast could not be shown in the current study. However, as feeding intolerance did not increase during the condensed feeding periods, the nutritional intake was probably limited by the prescription of nutrition and interruptions. More research is needed to determine the optimal level and duration of clinically relevant ketosis and the best method to achieve this.
摘要：
目的：重症患儿日夜喂养，假设这可以提高肠内耐受性和实现营养目标的可能性。以前表明，禁食反应，反映在酮症增加，至少部分解释了延迟开始补充肠外营养的有益结果。这项研究旨在调查过夜禁食是否会增加酮症，并且在重症儿童中是否可行且安全。
方法：儿科重症监护（ContInNuPIC）中的持续与间歇性营养研究是一项随机对照试验，在荷兰的三级转诊儿科重症监护病房（PICU）中进行。危重患儿（足月新生儿-18岁），预期PICU停留时间≥48h，依赖人工营养，有资格。参与者被随机分配（1：1，按年龄组分层）到间歇喂养，在8至12小时的与年龄相关的夜间喂养中断，或连续喂食，白天和黑夜的喂养管理。在这两组中,追求类似的每日热量目标。对于一岁以下的儿童，在禁食期间提供强制性少量葡萄糖输注.主要结果是可行性，定义为两种情况(1)：患者每日最高酮(3-β-羟基丁酸，BHB)在每个隔夜期间的水平，和(2)：关于每日热量摄入的非劣效性，使用两部分混合效应模型进行检查，预定义的非劣效性为33%，在意向治疗分析中。该研究已在荷兰试验登记册（NL7877）中注册。
结果：在2020年5月19日至2022年7月13日之间，140名危重病儿童，中位数（第一四分位数；第三四分位数）年龄0.3（0.1；2.7）岁，随机分为间歇喂养（n=67）或连续喂养（n=73）。在间歇喂养组中,BHB水平显着升高（中位数0.4（0.2；1.0）与0.3(0.1;0.7)mmol/L,p<0.001)。间歇喂养组的总热量摄入量与连续喂养组的总热量摄入量之比并非始终显着超过0.67，因此没有证明非劣效性。没有严重，耐药的低血糖事件，也没有发生与干预相关的严重胃肠道并发症，断断续续喂养组的喂养不耐受发生率并不高于连续喂养组。
结论：与昼夜喂养相比，对1岁以下儿童进行间歇喂养,通宵快速和强制性葡萄糖输注会略微增加酮症,并且在危重儿童中不会导致更多的低血糖事件.因为关于每日热量摄入的非劣效性没有得到证实，在当前的研究中无法显示过夜禁食的可行性。然而,由于在冷凝喂养期间喂养不耐受没有增加，营养摄入可能受到营养和中断处方的限制。需要更多的研究来确定临床相关酮症的最佳水平和持续时间以及实现这一目标的最佳方法。
方法：儿科重症监护（ContInNuPIC）中的持续与间歇性营养研究是一项随机对照试验，在荷兰的三级转诊儿科重症监护病房（PICU）中进行。危重患儿（足月新生儿-18岁），预期PICU停留时间≥48h，依赖人工营养，有资格。参与者被随机分配（1：1，按年龄组分层）到间歇喂养，在8至12小时的与年龄相关的夜间喂养中断，或连续喂食，白天和黑夜的喂养管理。在这两组中,追求类似的每日热量目标。对于一岁以下的儿童，在禁食期间提供强制性少量葡萄糖输注.主要结果是可行性，定义为两种情况(1)：患者每日最高酮(3-β-羟基丁酸，BHB)在每个隔夜期间的水平，和(2)：关于每日热量摄入的非劣效性，使用两部分混合效应模型进行检查，预定义的非劣效性为33%，在意向治疗分析中。该研究已在荷兰试验登记册（NL7877）中注册。
结果：在2020年5月19日至2022年7月13日之间，140名危重病儿童，中位数（第一四分位数；第三四分位数）年龄0.3（0.1；2.7）岁，随机分为间歇喂养（n=67）或连续喂养（n=73）。在间歇喂养组中,BHB水平显着升高（中位数0.4（0.2；1.0）与0.3(0.1;0.7)mmol/L,p<0.001)。间歇喂养组的总热量摄入量与连续喂养组的总热量摄入量之比并非始终显着超过0.67，因此没有证明非劣效性。没有严重，耐药的低血糖事件，也没有发生与干预相关的严重胃肠道并发症，断断续续喂养组的喂养不耐受发生率并不高于连续喂养组。
结论：与昼夜喂养相比，对1岁以下儿童进行间歇喂养,通宵快速和强制性葡萄糖输注会略微增加酮症,并且在危重儿童中不会导致更多的低血糖事件.因为关于每日热量摄入的非劣效性没有得到证实，在当前的研究中无法显示过夜禁食的可行性。然而,由于在冷凝喂养期间喂养不耐受没有增加，营养摄入可能受到营养和中断处方的限制。需要更多的研究来确定临床相关酮症的最佳水平和持续时间以及实现这一目标的最佳方法。
