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重症患者营养治疗: ICU, ICU后期和长期恢复期的实践指南

Chu • • 文献摘要 • 阅读 2426

Zanten et al. Critical Care. 2019; 23: 368

背景

       ICU不断进步的生命支持治疗能够改善患者预后, 让以往无法存活的患者能够存活下来. ICU医学的不断革新使患者在院死亡率逐年下降[1]. 但是, 许多ICU「幸存者」在转出ICU后并不能回到家庭过上自主功能的生活, 而是转至康复机构或是护理院, 对于他们是否能够有生活质量(QoL)其实并不清楚[2]. ICU存活患者遭受严重而长久的功能障碍的人数不断增长[2, 3]. 许多ICU患者可能出院后转到急性护理后机构并产生巨大的费用(在美国约为350万美元/功能性幸存患者)[4]. 残障十分常见, 约65%的ARDS幸存者存在明显的功能限制[2]. 所以…「我们到底是在制造幸存者, 还是受害者？」Needham等在2012年同意推荐使用重症监护后综合症(PICS)这个概念来描述重症患者中新发的或是进一步恶化的身体, 认知或是精神健康上的问题, 这些问题在急性监护的住院期间及之后持续存在[5]. 至此, 无论是政府机构还是ICU协会均推荐优先开展ICU后QoL相关的研究[6]. 为改善功能和QoL预后, 在ICU及恢复期间能够迅速开展的一项重要而经济的措施便是优化营养治疗。患者在严重疾病和恢复期的代谢状态随着病程和能量消耗及氮丢失不断发生变化, 因此要掌握好营养治疗的合适时机和最佳剂量[7]. 既往研究报道了充足喂养和预后之间的关系, 因此营养治疗十分重要[8]. 目前对于ICU存活患者的能量和营养需求几无文献报导, 并且目前所知的在ICU住院期间及出院治疗营养治疗实践, 表现相当糟糕[9, 10]。

本文旨在基于近期文献和指南, 为ICU住院, 转出ICU后以及长期恢复期患者的营养治疗提供实践性指南. 讨论宏营养素(热量和蛋白)提供时机和个体化的重要作用. 

 

ICU住院期间的营养治疗

欧洲临床营养和代谢协会(ESPEN)最近发表了重症患者营养治疗的循证指南[11]. 推荐早期肠内营养(EEN), 优于延迟肠内营养(EN)和早期肠外营养(PN). 延迟EN的理由很少(表1).

重症患者营养治疗: ICU, ICU后期和长期恢复期的实践指南

休克患者合适启动EEN目前仍存争议, 在初期血流动力学稳定即可开始EN, 无需等到血管活性药物停用之后方才启动EN[12, 13]. NUTRIREA-II研究中严重休克患者「强制」EEN发生内脏缺血和胃肠道不耐受的风险增加[14]. 然后在最近NUTRIREA-II的事后研究发现EEN组患者入ICU三天后瓜氨酸(citrulline)水平更高(反映的是肠细胞的量), 提示即使对于严重休克患者EEN对于肠道粘膜也是有益的[15].

热量的逐步增加

重症早期的代谢的病理生理学特点表现为炎症反应, 能量消耗增加, 胰岛素抵抗, 以及分解代谢反应, 导致能量储备如肝糖原(葡萄糖), 脂肪(脂肪酸)和肌肉(氨基酸)产能. ICU患者的喂养和健康人存在明显不同[16]. 重症早期的内源性产能并不能被营养治疗消除, 所以推荐在数天内逐步加量防止过度喂养[17]. 间接测热法检测到的ICU住院(早期)所达到的能量目标百分比和能量消耗(EE)之间的关系进一步说明了这一点. Zusman和Weijs发现的U型关系提示能量摄入占测得EE的70-80%为最佳, 而摄入过低或过高病死率均增加[8, 18].

但是这种U型关系在解释比较容许性低热量喂养和正常热量喂养的PERMIT研究结果, 以及比较高热量喂养和正常热量喂养的TARGET研究结果中显得不那么明确[19, 20]. 在这两项大型随机对照研究(RCT)中, ICU住院早期的低, 正常及高热量喂养的相关临床终点之间无明显差异. 重要的是在这些研究的研究组中蛋白摄入是相同的. 这些RCT研究的结果似乎和观察性研究的发现相矛盾. 但是在这些RCT中, 能量目标是通过公式计算而不是间接测热法测得. 公式计算并不精确, 所以在研究组中均可能出现过度喂养和喂养不足. 在PERMIT研究中, 两组间热量摄入的差别很小(约11 vs. 16 kcal/kg/天), 可能由于过小而无法检测出差异[21]. 另一种推测是在TARGET研究中, 两组患者分别在U型关系的上升支和下降支, 所以两组间病死率无差异.

目前的数据提示, 早期应当避免过度喂养, 而在蛋白摄入相似的前提下低热量和正常热量喂养患者预后无明显差异. TARGET和EAT-ICU研究均发现早期激进的能量摄入会导致高血糖发生率增高并且需要大剂量的胰岛素治疗[20, 22]. 虽然需要避免长期热量不足, 但接受有限不足(入ICU后第一周为20-30%)似乎是最佳的. 强烈推荐使用间接测热法估算ICU患者在初步抢救之后的热量目标[11].

再喂养综合征和低磷血症

再喂养综合征(RFS)特征性表现为一段时间禁食之后再次摄入营养所导致电解质改变, 目前仍缺乏明确定义, 但对于ICU患者最显著特征为再喂养之后出现的低磷血症(营养治疗开始72小时内低于0.65 mmol/L)[23-25]. 研究表明在2-3三天内限制热量在500 kcal/天或是低于热量目标的50%对于防止RFS造成的死亡相当重要[24, 25].

为何蛋白质对于重症患者至关重要？

肌肉是内源性氨基酸的主要来源, 患者入ICU时的肌肉量和重症患者的预后呈正相关[26]. 对于MODS患者, 入ICU前10天的分解代谢反应最多可使肌肉量减少达到1kg/天[27].

机制性研究发现给予高剂量蛋白对于肌肉量的丢失和肌肉蛋白合成具有有益的影响[28]. 许多观察性研究都发现给予较多蛋白和蛋白摄入较低相比患者的致病率和病死率具有降低[8, 29-33]. 但是大剂量蛋白给予的RCT研究数量较少, 并且对于功能及临床结局的影响有限或是阴性的[22, 34-38]. 急切需要更多的证据来高剂量蛋白给予和预后改善相关[39].

导致不一致或是阴性的结果的相关因素可能包括实验设计, 热量给与和过度喂养之间的相互作用, 或再喂养综合征, 或是给予营养的剂量、组成成分和时机[28]. 另外最近的研究如PROCASEPT研究也提示蛋白质对脓毒症和其他ICU患者的预后影响可能是不同的[18, 40].

蛋白质的给予时机和逐步增加

在比较早期和晚期补充性肠外营养(SPN)的EPANIC研究的事后分析中发现, 在极早期高蛋白的摄入和患者不良预后相关, 这可能也是另一种解释[41]. 这在另一项回顾性的PROTINVENT研究中也得到了证实, 虽然在调整了相关变量后摄入蛋白量低于0.8g/kg/天的患者6个月死亡率最高, 但在前三天给予高蛋白的患者死亡率也是增高的[42, 43].

一般认为蛋白和喂养能抑制自噬, 这是一种细胞内清除的重要机制. 但这是否能够阻止进入自噬不足的状态仍有争议[28]. 最近一项回顾性研究并没有发现ICU住院早期给予蛋白的不良影响, 反而能改善60天生存率. 这项研究中前三天给予了中等量的蛋白[44]. 基于这些有限的信息和无害原则, 推荐逐步增加蛋白目标[11, 45]. 这同样适用于热量摄入, 几天内逐步增加肠内营养的目标(图1). 根据ESPEN指南, 逐步增加后的蛋白目标至少为1.3g/kg/天[11].

重症患者营养治疗: ICU, ICU后期和长期恢复期的实践指南

如何达到蛋白质目标？

在重症患者中有计划有步骤的逐步实行能够更好的完成蛋白质目标(表2). 这种方法基于的第一步就是优化EN. 但达到蛋白质目标常伴有过度喂养, 这在临床上是富有挑战的. 大部分的鼻饲营养(以及场外营养制剂)蛋白质和能量比值都是低的. 最近正在进行一项国际随机对照研究比较了基于整蛋白更高蛋白质/能量比值和正常能量高蛋白制剂肠内营养[48]. 使用这种新制品, 第五天的蛋白摄入能够达到1.5g/kg/天, 检测血液氨基酸浓度明显高于对照组(平均蛋白质摄入0.75g/kg/天). 这项研究清楚的表明使用标准高蛋白制剂并不能达到1.0-1.2g/kg/天的蛋白质摄入目标. 增加蛋白摄入的其他方法包括使用肠内蛋白质补充或是补充静脉氨基酸注射液.

重症患者营养治疗: ICU, ICU后期和长期恢复期的实践指南

 

ICU中应当使用整蛋白还是水解蛋白制剂？

目前文献没有证据表明预消化或是水解肠内营养制剂比整蛋白制剂的耐受性更好[52]. 在一些研究中, 和多聚蛋白相比水解蛋白的耐受性更差达到目标水平更低[53, 54]. 目前不推荐常规使用亚成分配方[49]. 但是对于特定患者, 存在肠细胞量减少风险及肠道功能障碍, 特别是休克或是脓毒症患者亚成分制剂是否更好需要进一步的研究.

SPN的时机

荟萃分析和近期指南均不推荐早期, 也就是3-7天之前启动补充性肠外营养(SPN)[11, 50]. 仅在有理由延迟肠内营养及高营养风险的患者中考虑早期PN[11, 49]. SPN可能因为存在过度喂养的风险导致感染增加[55]. 但最近的TOP-UP研究表明对于过低及过高BMI具有高营养风险的ICU患者, SPN对于通过日常生活动能力量表(Barthel Index)检测的功能性恢复是有益处的(p < 0.08)[51]. 对于营养不良或低BMI患者实行早期SPN对于功能性预后的影响需要进一步研究明确.

营养监测

目前并无研究比较有监测和无监测的营养治疗. 但检测异常值潜在有害得到国际专家的一致认同[56]. 推荐使用适合当地的标准运作程序随访EN和PN. 临床体征, 实验室指标(包括血糖、电解质、甘油三酯和肝功能), 及监测能量消耗和身体成分对于预防和检测营养相关的并发症十分重要[56].

 

转出ICU住院期间的营养治疗

在这一时期并没有关于热量和蛋白质摄入的正式推荐或指南. 但需要优化热量和蛋白摄入增强功能性肌肉量的修复, 防止其进一步的丢失. 很可能需要显著的热量/蛋白补充来恢复丢失的肌肉量改善QoL. 恢复期的间接测热法研究显示能量需求明显增加, 总EE(TEE)增加至静息EE(REE)之上约1.7倍[57]. 脓毒症后的第二周, TEE为3250kcal/天或47kcal/kg/天. 在年轻创伤患者中, 甚至观察到伤后两周高达4120kcal/天或59kcal/kg/天的TEE. 在一项回顾性研究中看到了ICU期间更高蛋白质补充和患者生存之间的关系：出院后90天死亡率降低了17%. 但是目前尚无病房患者营养摄入的数据.

目前尚无转出ICU患者蛋白质目标的数据; 然而考虑转出ICU患者一般年龄较大, 许多还很虚弱, 认为这些患者蛋白合成代谢的阈值较高(合成代谢抵抗). 考虑蛋白摄入为1.5-2.5g/kg/天.

 

转出ICU患者营养摄入为多少？

对于转出ICU的患者, 最近研究报道平均自主经口摄入的热量为700kcal/天, 而在整个转出ICU的研究阶段, 整体研究人群摄入的热量/蛋白质低于需求的50%[59].

另一项研究评估了17名转出ICU的患者住院期间的营养治疗情况. 病房的营养治疗低效并且和目前推荐意见并不一致. 优化治疗的巨大障碍是组织上的问题[60]. 一项纳入32名患者稍大的队列研究评估了转出ICU后患者的代谢状况和营养摄入[10]. 每日的热量需求约为2000kcal及112g蛋白质. 但营养治疗的摄入明显不足, 仅有62%患者热量达标, 54%患者蛋白质达标. 患者主要通过经口及胃肠管喂养. 对于仅使用口服营养而无口服营养补充制剂(ONS)的患者, 摄入进一步降低(40%).

最近未发表数据提示转至普通病房的ICU患者在拔除了胃管之后热量摄入降低了目标值的22%而蛋白摄入降低了目标值的27%(Van Zantan, 个人联系). 这些数据提示作为替代性日常护理, 需要考虑长时间保留胃管直至经口营养摄入足够为止.

而最近来自布鲁塞尔的数据也支持这些发现：追踪随访在2018年12名转出ICU患者的整个住院时间. 客观记录这些患者的营养需求、治疗开立和营养的给予. 计算营养是否足够(图2[61]). 患者之间存在巨大的差异, 大部分患者喂养不足；但同时也存在过度喂养. ICU存活患者在ICU之外花费的时间大于ICU内的时间, 所以急切需要这些患者代谢速率、营养是否足够以及营养治疗效果方面的数据. ICU存活患者在普通病房中热量和蛋白摄入都是低的, 而如此之低摄入和需求比值在临床上是无法接受的.

重症患者营养治疗: ICU, ICU后期和长期恢复期的实践指南

转出ICU后的营养康复

重症之后患者的食物摄入的生理调节功能会随着时间逐步恢复. 许多功能改变都会导致在恢复期营养摄入不足. 这些改变包括空腹期的无食欲；进食期包括吞咽困难；以及进食之后的胃排空障碍, 胃动力不足及腹胀[62].

目前急切需要营养治疗实践、障碍(如气管插管后吞咽困难发生率高)和可能的解决方案进一步的研究数据. 虽然信息有限, 目前的研究结果均强调转出ICU患者在出院之前密切监测营养摄入, 以及指导护理人员和医疗保健专业人员为患者在家中提供最佳的营养治疗的重要性.

出院后及恢复期的营养治疗

ICU转出的患者在出院之后是否能够经口摄入足够的热量和蛋白质, 在家中或是康复机构达到最佳的恢复. 另外, 我们需要花一点时间阅读一下明尼苏达饥饿研究(Minnesota Starvation Study)的重要结果[7]. 即使是健康受试者也需要显著的能量(3000-4500kcal/天)和高达1.5-2.5g/kg/天的蛋白质来恢复饥饿后丢失的肌肉量.

患者转出ICU后出现明显的力量下降和肌肉量丢失在相当一段时间对于热量和蛋白质的需求都是增加的, 可持续数月甚至数年[63]. 对于这一点理解不深刻会导致患者长期预后和QoL极差.

多少护理流程或是患者能够在没有经口蛋白和营养添加制剂的补充下达到这个明确的目标？大量数据表明对于ICU存活患者出院后治疗, 经口营养补充制剂(ONS)是必须的. 不同住院患者的荟萃分析提示ONS能够降低病死率, 减少住院并发症, 降低再住院率, 减短住院时间及降低住院费用[64-67]. 一项纳入了724000患者匹配未接受ONS治疗的对照组的大型医院数据分析发现ONS的使用能够降低21%的医院LOS, 在ONS每花费1美元将节省52.63美元的住院费用[68]. 最后, 近期一项纳入652名患者研究出院后高蛋白ONS(HP-ONS)联合β羟基β丁酸甲酯(HP-HMB)和安慰剂ONS对于住院老年营养不良患者(主观整体营养状况评量表, Subjective Global Assessment, SGA B或C级)的影响. 这个明确对于出院后患者的研究证明了HP-ONS联合HMB和安慰剂相比能够降低约50%的90天病死率(4.8% vs. 9,7%; 相对危险度 0.49; 95%可信区间0.27-0.90, p=0.018). 为防止一例出院后患者死亡所需要的治疗人数为20.3人(95% CI 10.9-121.4)[69]. 患者从脓毒症恢复及在ICU期间并不会得到足够的热量和蛋白以达到最佳的恢复, 因此对于所有ICU存活患者在出院之后均强烈推荐使用HP-ONS至少3个月(甚至可到两年). 在部分患者中, 需要长期考虑胃管或是肠外营养.

合成代谢/抗分解代谢药物的重要作用

持续性数月到数年的分解代谢及高代谢状态对ICU存活患者也是挑战之一. HP-ONS研究和其他的最近综述强调了合成代谢和抗分解代谢药物的重要性, 如普萘洛尔、氧甲氢龙和其他的能够增加干肌肉重量的药物, 对于恢复ICU转出后QoL和生存具有重要的作用[70]. 目标性营养包括足够的蛋白质给予和『肌肉恢复目标性』合成代谢/抗分解代谢药物联合锻炼能改善QoL[71].

普萘洛尔

最近一篇综述介绍了烧伤患者中常规使用合成代谢/抗分解代谢药物的情况[70]. 使用普萘洛尔逆转重症患者持续性高分解代谢有着丰富的经验[72]. 这些数据显示普萘洛尔对于严重烧伤患者面临的严重而广泛的分解代谢是唯一促进合成代谢的药物. 最近的研究表明低剂量的心脏选择性的β受体阻滞剂虽然能够逆转分解代谢, 但尚不能降低ICU患者能量消耗[73]. 普萘洛尔对于转出ICU患者的影响还需要进一步的研究支持.

睾酮和氧甲氢龙

也许更令人激动的是不断增长的文献支持的睾酮和氧甲氢龙在部分患者中的安全性、临床有效性和益处. 氧甲氢龙是睾酮中最具有合成代谢的药物, 口服氧甲氢龙十分安全, 长期使用对肝酶的影响很小. 氧甲氢龙显示能够降低烧伤患者的病死率[74]. 最近发表的一项大规模观察性研究纳入>43000名睾酮缺乏的患者(几乎是七天内所有的ICU住院患者), 在给予补充睾酮制剂后全因心血管事件降低33%, 卒中风险降低28%, 从而消除了睾酮对心血管和血栓风险的担忧[75]. 最近一项关键性荟萃分析结果提示睾酮能够增强心衰患者对于运动的耐受性[76]. 在ICU住院7天及以上的患者需要考虑检测睾酮水平, 通常是降低的甚至无法测得。替代治疗一般为环戊丙酸睾酮(testosterone cyprionate)(~200mg IM q2weeks), 睾酮贴(~ 4mg贴剂)或口服氧甲氢龙(10mg BID)。

这一领域急切需要除烧伤患者以外的临床研究, 目前的纳入三项研究的荟萃分析并未提示明显的益处, 除了预防ICU住院期间高血糖[77]。

结论

重症早期的急性的代谢改变, 炎症和营养之间的关系十分复杂. 新的研究提示早期热量和蛋白的逐步增加喂养对于防止过度喂养和高热量摄入导致再喂养低磷血症具有重要作用. 在过了4-7天这个期之后, 高蛋白和足够的热量对于防止进一步的肌肉量丢失和功能丧失具有重要作用.

在ICU转出后, ICU存活患者特殊的代谢状况和营养需求仍然未知需要进一步的研究. 少量数据提示患者转出ICU进入普通病房后营养治疗实践相当糟糕, 还有很远的路要走.

出院之后我们必须保证患者实行高蛋白目标, 无论是通过长期的胃管鼻饲还是增强性口服营养制剂. 另外恢复期合成代谢/抗代谢药物等的营养代谢治疗亟需研究支持.

改善患者长期的ICU预后, 让患者回归正常生活, 在这场战争中必须考虑在所有时期最佳的营养和代谢治疗, 保证正确的患者在正确的时间, 得到正确的营养治疗.

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本文荟萃自 重症文献翻译转运站，只做学术交流学习使用，不做为临床指导，本文观点不代表数字重症立场。

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