静息能量代谢监测对创伤、脓毒症目标能量指导的临床研究
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摘要
研究背景
营养支持是救治创伤、脓毒症患者的重要手段之一。但由于创伤、脓毒症病情复杂常使营养支持的实施结果并不理想。在ICU仍高达40%的患者发生营养不良。而造成营养不良的原因与不恰当的能量供应有着密切的关系。无论营养过度或营养不足均可使住院时间延长,机械通气时间延长,并发症增多。营养不足可使机体免疫功能低下,伤口愈合减慢、易发生院内感染；而营养过度使机体脏器负担加重,脂肪在肝脏的堆积,易出现高脂血症、高血糖及低磷酸血症,从而使免疫功能受损。而恰当的营养支持可以改善预后,提高机体免疫力,减少并发症。同时,机体在创伤、脓毒症的发生、发展过程中常伴随着一系列细胞因子、炎性介质的大量释放,表现为氧耗量增加、蛋白分解增强、心输出量增多、糖皮质激素增加、儿茶酚胺增加,这些代谢的改变受细胞因子的调节,并与预后及疾病严重程度相关。此时患者对营养物质的利用及合成也发生改变,在应激状态下如何进行恰当的营养支持,仍是一个临床尚没能很好解决的问题。造成这样的原因与临床上对于患者目标能量的制定仍无统一的标准有一定的关系,不恰当的能量供给可造成营养过度或营养不足,因此,制定一个适合患者的目标能量值就显得非常重要。
对于危重症营养支持中目标能量的确定,欧洲(ESPEN)及美国(ASPEN)肠外肠内协会推荐的既有以测量静息能量代谢值(MREE)为目标能量值,又有以体重或预计能量代谢公式计算值为目标能量,表明目标能量的确定仍存在不一致的观点,并且有关目标能量确定的指南推荐以专家共识为主,缺乏循证医学支持。
静息能量代谢测定的方法有直接测定法及间接测定法,其中,呼吸间接测热法(indirect calorimetry, IC)是临床上较常用的方法,它是根据能量守恒定理和化学反应的等比定律来监测能量代谢。人体在消耗碳水化合物、脂肪、蛋白质会产生热量,在提供能量的同时,也相应地消耗一定量的氧气并产生一定量的二氧化碳。根据此原理,测量一定时间内氧气的消耗量(VO2)及二氧化碳的产生量(VCO2),可根据Weir公式计算出这一时间内的能量消耗,推算出24小时内静息能量消耗。目前认为,间接测热法是测量静息能量代谢的金标准。虽然在临床上可实现静息能量代谢的监测,但测定的静息能量代谢值如何指导临床营养支持的应用以及其测量值是否可做为目标能量提供热卡,目前在国内外并无类似的研究及确切的结果。
目的：
主要目的：观察以不同目标能量值提供能量对预后的影响。监测静息能量代谢变化,并根据静息能量代谢值提供不同层次的能量供给,观察不同水平热卡的能量供给对创伤、脓毒症28天、60天死亡率的影响,观察哪种能量供给方案更适合危重病目标营养的制定,提出更为确切的方案,从而指导临床营养的实施。
次要目的：
1、观察创伤、脓毒症静息能量代谢特点及与预计公式之间的一致性分析及对预计公式与静息能量代谢进行相关性分析。
2、观察不同热卡的能量供给对创伤、脓毒症机械通气时间、免机械通气时间的影响。
3、观察不同热卡的能量供给对创伤、脓毒症营养指标、肝功能、免疫功能、炎性因子的影响。
方法：
第一部分创伤、脓毒症患者静息能量代谢的特点、监测与评估
选择2011年6月1日至2013年12月31日期间广州军区陆军总医院重症医学科及武警广东总队医院重症监护科收治的脓毒症、创伤(包括手术后)病人。记录患者入住ICU后基本病情资料,测量其静息能量代谢值,并利用各种公式(H-B公式、H-B×1.2公式、ACCP公式、Ireton-Jones92公式、Ireton-Jones97公式、Mifflin公式)推算出预计的能量代谢值。对公式预计值与静息能量代谢实测值进行偏倚性分析；分析各种公式预计值准确性；分析创伤、脓毒症患者静息能量代谢早期分布状态；对公式预计的能量代谢值与实测的静息能量代谢值进行一致性分析,评估临床可接受范围内的公式准确率；对静息能量代谢实测值与公式预计值进行相关性分析。
第二部分不同目标能量值提供能量对创伤、脓毒症患者预后及并发症的影响
选择2011年6月1日至2013年12月31日期间广州军区陆军总医院重症医学科及武警广东总队医院重症监护科收治的脓毒症、创伤(包括手术后)病人。其中对253例进行了研究。根据随机分组表分为4组,其中1组为以ACCP公式25kcal/kg/天为目标能量值；2组为以静息能量代谢值的80-89%为目标能量值；3组为静息能量代谢值的90-110%为目标能量值；4组为静息能量值110%以上为目标能量值。所有脓毒症患者在入ICU后均接受原发病常规治疗。病情平稳后24小时内行肠内营养支持治疗(EN),目标能量值达标时间为4-5天,如未达标则予以肠外营养(PN)补充。蛋白给予量为1.0g/kg/d。记录每日给予能量的量、途径、蛋白给予量、开始喂养时间,记录每周累积能量平衡及转出ICU或出院(死亡)时累积能量平衡；记录患者在ICU停留时间及住院时间、28天无需机械通气时间、28天、60天死亡率,进行60天生存分析；记录患者治疗前(day0)、治疗后第一天(day1)、治疗后第三天(day3)、治疗后第五天(day5)、治疗后第七天(day7)或转科、死亡时(discharge)的APACHE II评分、SOFA评分；测量患者在营养治疗前(day0)、治疗后第七天(day7)、第十天(day10)、第十四天(day14)的前白蛋白、视黄醇结合蛋白、转铁蛋白水平、肝功能指标；监测患者在营养治疗前(day0)、治疗后第七天(day7)免疫因子(CD14+/HLA-DR)表达的改变。
第三部分不同目标能量值提供能量对创伤、脓毒症患者炎性因子水平的影响
选择2011年6月1日至2013年12月31日期间广州军区陆军总医院重症医学科及武警广东总队医院重症监护科收治的脓毒症、创伤(包括手术后)病人共有45例患者纳入研究。按前期分四组及对照组。对照组为同期入院患者,非脓毒症外科患者(APACHEII评分低于12分)。记录病情指标,记录检测患者在营养治疗前(day0)、治疗后第七天(day7)血清炎性因子的变化(IL-6、IL-10、 TNF-α、IL-4)。记录促炎/抗炎反应平衡的变化(IL-6/IL-10、IL-10/TNF-α)。
结果：
1创伤、脓毒症患者静息能量代谢的特点、监测与评估
1.1静息能量代谢实测值与各种预计公式计算值对比
ACCP法估计的能量代谢值与间接测热法测得的实测值比较无偏倚,评估准确率略高,差异无统计学意义(t=1.534, P=0.126)。而其他公式预计值与实测值比较差异有统计学意义,其中Ireton-Jones92估计值最高,与实测值比较差异有统计学意义(t=12.114, P=0.000); H-B公式、Mifflin公式所估计的能量代谢值均低于实测值,与实测值比较差异有统计学意义(t分别为6.478、7.938,P均<0.001)；Ireton-Jones97公式与H-B×1.2系数公式评估值分别与实测值比较,差异有统计学意义(t值分别为4.909、2.657,P值分别为0.000、0.008)。
1.2创伤、脓毒症静息代谢特点
创伤、脓毒症患者有50%以上处于高代谢状态,而正常代谢范围在22.22%-22.83%,低代谢状态为22.73%-27.78%,三组间比较无显著性差异(χ2=0.706,P=0.951)。
1.3各种公式与实测值之间一致性分析：
大多数公式在95%界限范围内的一致性较高,均为95%以上,其中ACCP公式、Ireton-Jones92公式一致性达97%以上,但一致性界限范围过大,为临床上不能接受范围,而±10%MREE (-195.46,195.46) kcal/day为临床可接受范围,在此范围内再进行一致性分析,各公式的一致性符合率明显下降,ACCP公式、H-B公式及Mifflin公式一致性分别为27.27%、27.67%、27.67%,而Ireton-Jones92公式一致性为18.18%。
1.4实测值相关性分析
各种公式预计值与实测值均存在相关性,差异有统计学意义,但相关关系并不密切。其中Mifflin相关性略强,r值为0.474,而ACCP公式相关性较低,r值为0.317,P均<0.001。而静息能量代谢与体重、BMI值呈正相关,r、P分别为0.388、0.000及0.238、0.008；与NRS2002负相关,r=-0.143,P=0.023；与APACHE II无相关性,P值=0.511。
2不同目标能量值提供能量对创伤、脓毒症患者预后及并发症的影响
2.1各组热卡值及蛋白摄入比较
各组第一周摄入热卡数比较,差异有统计学意义(F=16.366,P=0.000),组间多重比较显示80-89%组第一周平均摄入能量、第一周累积摄入、平衡住院期间摄入能量平衡均明显低于其他三组,四组之间第一周平均蛋白摄入比较,差异无统计学意义(F=2.028,P=0.110)。
2.2不同目标能量组提供能量对在ICU停留时间、机械通气时间的影响
不同目标能量组对机械通气时间、ICU停留时间、住院时间,差异无统计学意义(F值分别为0.543,0.896,1.481,P值分别为0.654、0.445、0.220),而28天内免机械通气时间差异有统计学意义(F=2.763,P=0.043),其中90-110%、25kcal/kg组免机械通气时间较另两组长,组间多重比较差异有统计学意义(P<0.05)。
2.3不同目标能量组28天死亡率、60天死亡率的比较
90-110%组28天死亡率12.1%,低于另三组,其余各组死亡率为23.3%以上,但各组28天死亡率比较,差异无统计学意义(χ2=6.685,P=0.083)。60天死亡率分析结果显示所有各组死亡率均上升,其中,90-110%组其死亡率上升至21.5%,而另外三组则升至40%以上,各组比较差异有统计学意义(χ2=12.712,P=--0.005)。
2.460天Kaplan-Meier生存分析：
经Kaplan-Meier法进行60天生存分析：结果显示90-110%组累积生存率高于其他三组,差异有统计学意义(χ2=10.375,P=0.016)。
2.5治疗前后营养指标的变化：
随着时间的推移,视黄醇结合蛋白逐步升高,不同时间点之间有显著性差异(F=I0.126,P=0.000),其中>110%组在第十四天达到最高值。转铁蛋白在营养治疗前后不同时间之间有显著性差异(F=4.611,P=0.016),前白蛋白也随着时间的推移而逐渐上升,与营养开始前比较,差异均有统计学意义(F=3.602,P=0.031)。
2.6治疗前后免疫功能的变化：
在一周内营养支持后各组CD14+/HLA-DR的表达无明显变化,差异无统计学意义(F=1.992,P=0.166),治疗一周后各组之间比较,差异有统计学意义(F=3.739,P=0.016),其中80-89%组、90-110%均有不同程度的上升(P<0.05)。从不同营养支持途径分析,CD14+/HLA-DR表达在营养治疗前后无不明显变化,而给予肠内营养、肠内营养与肠外营养联合应用的患者CD14+/HLA-DR表达增加,肠外营养途径的CD14+/HLA-DR表达下降,三组比较差异有统计学意义(F=6.612,P=0.003)。
3不同目标能量值提供能量对创伤、脓毒症患者血清炎性因子水平的影响
3.1血清炎性因子的变化：
IL-4、IL-10、TNF-α:实验组与对照组比较差异有统计学意义(F值分别为8.684、11.974、348.77,P值均小于0.001)。IL-6：各组比较差异无统计学意义(F=0.689,P=0.598)。各实验组组间比较,差异无统计学意义(P>0.05)。其中TNF-α:实验组80-89%组与25kcal/kg组、>110%组比较差异有统计学意义(P均<0.05)：80-89%组与90-110%组比较,差异无统计学意义(P均>0.05)。
3.2各实验组营养治疗前后炎性因子的变化
IL-6：90-110%组营养支持治疗后IL-6水平下降,与治疗前比较差异有统计学意义(t=3.779,P=0.005),其余各组治疗前后差异无统计学意义(t值分别为1.606、-0.482、1.918,P值分别为0.147、0.643、0.091)。TNF-a:各组治疗前后比较差异无统计学意义(t值分别为1.296、-1.342、-0.199、-0.249,P分别为0.231、0.216、0.847、.0.810)。IL-4：25kcal/kg组、>110%组营养治疗前后对比差异无统计学意义(t值分别为0.337、-2.133,P值分别为0.745、0.065)；80-90%组、90-110%组营养治疗前后对比差异有统计学意义(t值分别为-2.730、-11.801,P值分别为0.026、0.000)。IL-10：各组营养治疗前后对比差异无统计学意义(t值分别为0.357、1.252、-0.292、0.605,P值分别为0.730、0.246、0.778、0.562)。3.3IL-6/IL-10的变化
治疗前各实验组与对照组比较差异有统计意义(F=12.489,P=0.000),多重比较,结果显示各实验组与对照组组间差异有统计学意义(P<0.05),各实验组之间差异无统计学意义(P>0.05)。治疗后不同组之间有显著性差异(F=11.843,P==0.000),其中实验各组与对照组,差异有统计学意义(P<0.05),其他实验各组差异无统计学意义(P>0.05)。各组治疗前后对比90-110%下降,与治疗前比较差异有统计学意义(t=4.007,P=0.004)。
3.4IL-10/TNF-a的变化
营养治疗后不同组间有差异(F=57.084,P=0.000),其中各实验组之间差异无统计学意义(P>0.05),而与对照组比较有显著性差异(P<0.05)。对照组营养治疗前后IL-10/TNF-α值比较差异有统计学意义(t=4.746,P=0.01),而其他实验组营养治疗前后对比无明显统计学差异(t值分别为0.803、0.541、-0.905、-0.599,P值分别为0.445、0.509、0.392、0.566)。
3.5炎性因子的相关性研究：
营养治疗前TNF-a、IL-6水平与APACHE II评分呈正相关(P均<0.001)；IL-4、IL-10与APACHE II评分呈负相关(P=0.009,P=0.000)。营养治疗后IL-6水平与实际供能呈负相关(P=0.041)；IL-10、IL-4及TNF-a与实际供能无相关性(P=0.332,P==0.098,P=0.230)。
结论
1创伤、脓毒症患者静息能量代谢早期紊乱,所有预计能量代谢公式均不能反映实际静息能量代谢状态,在临床可接受范围内的一致性更低,以公式预计值提供能量可能造成营养不足或营养过剩。
2以不同目标能量提供给能量短期内对患者预后影响不明显(28天),但对60天可产生影响,其中以静息能量代谢实测值90-110%的热卡供能可改善60天生存。不同目标能量的供给对患者机械通气时间、ICU停留时间及住院时间无影响,但对28天内免机械通气时间有影响,其中,给予静息能量代谢实测值90-110%的热卡可延长免机械通气时间。
3经过营养支持后所有能量支持组营养指标在10天后均有所改善,营养支持短期内对免疫功能无明显影响,但给予肠内营养及90-110%能量组CD14+/HLA-DR表达较其他组增加。
4促炎因子IL-6与能量供给呈正相关,适当的营养支持治疗可能可以通过减少部分促炎因子的释放来协助促炎/抗炎因子平衡,而短期的营养支持对抗炎/促炎平衡无明显调理作用。
Background:
Nutritional support is an important method in the treatment of trauma and sepsis patients. However, implementation of nutritional support often results in no satisfactory results due to its complicated co-morbility. Up to40%of ICU patients experience various degrees of malnutrition. The cause of malnutrition is closely related to inadequate energy supply. Both nutrition underfeeding and overfeeding could result in malnutrition. Underfeeding could lower immunological function, prolong wound recovery and increase nosocomial infectious morbidity; while overfeeding aggravates the burdens of organ, and increases the likelihood of steatosis, hyperlipidemia, hyperglycemia, low hypophosphatemia, and impairs immune function. Either underfeeding or overfeeding could prolong hospitalization, mechanical ventilation duration and raise associated complications. Appropriate nutritional support can improve prognosis, immunity, and reduce complications. But how to provide proper nutritional support is a debated issue which still lacks effective clinical standard. The lacking of clinically developed uniform standards to optimize patient's nutritional state contributes to malnutrition. Therefore, setting an optimal nutrition standard for patients is vital.
Indirect calorimetry (IC) is based on the energy conservation law of geometric theorems and monitor chemical reactions in energy metabolism. Through the consumption of carbohydrates, fat and proteins, the human body will produce heat, consume a certain amount of oxygen and produce a certain amount of carbon dioxide. According to this principle, by measuring the consumption of oxygen (VO2) and the release of carbon dioxide (CO2) in a preset time, with the Weir equation, the energy consumption could be calculated and the energy consumption of24hours could be speculated. To date, IC is considered as the golden standard in measuring resting energy expenditure, however, the application of IC in determining the optimal nutrition standard still lacks global similar prospective randomized controlled trials with positive results to support the hypothesis to use resting energy expenditure to determine the target energy.
With regards to setting optimal nutritional standard for critically ill patients, Europe (ESPEN) and the U.S.(ASPEN) guidelines recommend measuring resting energy expenditure (MREE) to derive the optimal nutritional state, and also using weight and energy metabolism estimation formula to calculate the target energy state, these recommended approaches relies mainly on the consensus of experts, supported by the lack of evidence-based
During and post trauma and sepsis, the human body will release a series of cytokines, and also experience in different degrees of increase in terms of oxygen consumption, Proteolysis, Cardiac output, Glucocorticoid and Catecholamine. The Utilization and synthesis of nutrients also changed, the traditional nutritional support could not offset the increase in catabolism and protein loss. Some cytokines such as TNF-a, IL-2, IL-6involved in the regulation of inflammatory reactions, the IL-6protein will induce the liver to prioritize the synthesis of Acute phase proteins (such as the C-reactive protein), thus Albumin, Pre-albumin, Transferrin and Immunoglobulin concentration decreases. The change of Pro-inflammatory cytokines and lower metabolism are associated with mortality.
Objective:
Primary endpoints:To observe the effect of different target energy value on prognosis. IC was utilized to measure changes in resting metabolic rate to provide different levels of energy supply. The effect of different caloric supply on28day,60day mortality rate of trauma and sepsis patients was observed. Which level of caloric supply is the most suitable for Critical patients were analyzed, so as to provide a more accurate strategy to instruct the clinical nutritional support implementation.
Secondary endpoints:
1. To observe the resting energy expenditure characteristic related to trauma, sepsis patients, to perform the consistency analysis between our value and predicted formula and to discuss the related factors of resting metabolic rate.
2. To observe the impact of different caloric supplement levels on the mechanical ventilation and ventilation-free days of trauma and sepsis patients.
3. To observe the impact of different caloric supplement levels on the nutritional indicators, liver function, inflammatory indicators, immune function and inflammatory cytokines in trauma and sepsis patients.
Methods:
Part1:The characteristic, monitoring and evaluation of resting energy metabolism in trauma and sepsis patients.
Patients with sepsis and trauma (including post-surgery) were included from2011/6/1to2013/12/31admitted to the ICU of Guangdong Armed policed Hospital. The characteristics of patients were recorded and the resting metabolic energy value was measured. The values of resting energy metabolism in various formulas were calculated. The bias analysis between the measured resting energy metabolism value and calculated formula value were performed and the accuracy was compared; the energy distribution were analyzed and the consistency analysis between formula estimation data and the actual measuring value of the metabolic energy level were processed to evaluate the clinical acceptable ranges. The correlation analysis between the two approaches were also conducted.
Part2:The impact on the outcome and complications under different target energy level in trauma and sepsis patients.
253cases of patients admitted to the ICU of Guangdong Armed policed Hospital were included from2011/6/1to2013/12/31and divided into four groups through randomization:group one used the ACCP formula of25kcal/kg/day as the target energy level; group two used the80-89%of the target energy level from the resting metabolic rate; group three using90-110%as target; group four using over110%. All patients were received conventional treatment, and enteral nutritional supports were administered within24hours under stable condition.4-5days were cost to achieve the target energy level, and if not, parenteral nutritional support was supplemented. Protein dosage is1.0g/kg/day. Daily support of energy level, protein level and administration method were recorded, along with administration time, accumulated energy balance weekly and the total energy balance when transferred out of ICU or out the hospital (deceased). The mortality rate on28day and60day, ICU stayed and total hospital stay, ventilation-free days within28day were recorded, and survival analysis of60day was performed. the APACHE II, SOFA score before treatment (day0), first day under treatment (day1), third day under treatment (day3), fifth day under treatment (day5), seventh day under treatment (day7) or after transfer out or discharge were calculated, and the pre-albumin, retinol binding protein, transferrin, liver function index level were detected before treatment (day0), seventh day under treatment (day7), tenth day under treatment (day10), fourteenth day under treatment (day14). Gauge the immune index(CD14+/HLA-DR) on before treatment (day0) and seventh day under treatment (day7).
Part3:The impact of different target energy level on the inflammatory cytokine levels in trauma and sepsis patients.
45cases of patients admitted to the ICU of Guangdong Armed police Hospital were included from2011/6/1to2013/12/31and were divided into the same four groups plus control group. The patients who enrolled in the control group were hospitalized during the same period without sepsis (APACHE II score<12). The characteristics were recorded, and the inflammatory cytokine levels (IL-6、IL-10、 TNF-α、IL-4) were measured on the day before nutritional support (day0) and seventh day under treatment (day7). The Pro-inflammatory/Anti-inflammatory balance (IL-6/IL-10、IL-10/TNF-a) was observed.
Result:
1. The characteristics, monitoring and assessment of resting energy metabolism in trauma and sepsis patient:
1.1Comparison of measured resting energy metabolism values with other calculated formula values:
The resting energy metabolism rate estimated by ACCP was not significantly different compared with indirect measuring values (t=1.534, P=0.126). Where other calculated formula values was significantly different(t=6.478、7.938, respectively and P<0.000) from indirect measuring value.
1.2. The characteristic of resting energy metabolism:
More than50%of trauma and sepsis patient manifested a hypermetabolic state, with22.22%-22.83%manifesting normal and the rest manifesting hypo-state. There was no significant difference among three groups (P>0.05).
1.3. The correlations between indirect measurement and different calculated formula values:
The majority of the calculated formula values had up to95%precision consistency in95%ranges, while ACCP and Ireton-Jones92formula indicated more than97%precision consistency. Due to the fact that large range outside the clinical acceptance, and±10%MREE (-195.46,195.46) kcal/day is more reasonable range, consistency analysis was re-performed, and the previous high precision were significant decreased with ACCP, H-B and Mifflin formula consistency of27.27%,27.67%and27.67%, respectively, and Ireton-Jones92consistency of18.18%.
1.4Direct measurement correlation analysis:
There was a significant correlation between various formula values and the direct measurement value (P<0.000), with Mifflin with r value of0.474to be strongest correlated and ACCP with r value at0.317to be weaker. While resting energy metabolism were positively correlated with body weight and BMI, and negatively correlated with NRS2002, and no correlation with APACHE II were observed (P=0.511).
2. The effect of different target energy levels on the prognosis and complications in sepsis and trauma patients.
2.1The comparison of calorie and protein intake:
There is a statistical significance in the initial week calorie intake in all groups (F=16.366,P=0.000).The average energy intake, the accumulative energy intake balance and the total energy balance during first week were much lower in group2than those of other three groups, while the average protein intake between the four groups during the first week were similar (F=2.028,P=0.110).
2.2Various target energy on ICU stay and mechanical ventilation duration:
There were no statistical significances of mechanical ventilation duration, ICU stay and total hospital stay in all groups (F value is0.543,0.896,1.481,P value is0.654,0.445,0.220,respectively), except for ventilation-free time within28day (F=2.763, P=0.043). The ventilation-free time within28day were much longer in90-110%and25kcal/kg group compare with the other two groups.
2.3Comparison of the28-day,60-day mortality rate.
The28-day mortality rate of the90-110%group (12.1%) was lower than the other three groups (>23.3%) with no significance. The60day mortality rate all increased, with90-110%group of21.5%and other three groups of more than40%, and the compassion was statistically significant (χ2=12.712,P=0.005).
2.460-Day Kaplan-Meier Survivability Analysis:
The60Day Kaplan-Meier analysis showed that the mortality rate was lower in90-110%group than those in other three groups, with statistical significance (χ2=10.375,P=0.016).
2.5The changes of nutritional indexes pre and post treatment:
With the pass of time, the level of Retinol binding protein raised gradually and significantly (F=10.126,P=0.000). The rise in80-89%group was not significant, while the other three groups observed remarkable increase. Transferrin and pre-albumin also rised significantly over time (F=4.611,P=0.016). While there was no difference among the4groups (F=0.411,P=0.868).
2.6The changes in immune functions pre and post treatment:
The CD14+/HLA-DR expressions in all groups were similar in first week (F=1.992, P=0.166) and increased significantly since second week (F=3.739,P=0.016) with the80-89%and90-110%group to be more distinct. Through analyzing the different nutritional support approaches, the CD14+/HLA-DR expressions in all groups changed little in first week, after one week of the treatment, the HLA-DR presentation was increased in EN group and mixed group combining EN and PN, while decreased in PN group, and the difference were statistically significant (F=6.612,P=0.003).
3. The impact of different target energy level on inflammatory cytokines levels in sepsis and trauma patients.
3.1The cytokine levels after treatment:
There were significant differences in IL-4and IL-10levels after treatment across the groups (F=6.766,P=0.000,and F=4.479,P=0.004). The IL-4levels in80-89%group were much different from those in90-110%group and25kcal/kg group (P<0.05), and those in>110%group were significantly different from25kcal/kg group and90-110%group (P<0.05). There was no difference in IL-4levels in90-110%group and25kcal/kg group (P>0.05). The IL-10levels were similar in4groups (P>0.05) and higher than that in control group (P>0.05). The IL-6and TNF-a levels were similar in all groups (F=0.617,P=0.653vs F=2.363, P=0.070).
3.2The inflammatory cytokine levels after treatment:
The IL-6levels in90-110%group decreased after treatment (t=3.779,P=0.005), while other groups observed non statistical significances (P>0.05). The TNF-a and TL-10levels were similar in all groups (P>0.05). The IL-4levels only in80-89%group and90-110%group changed significantly (P<0.05).
3.3IL-6/IL-10ratio:
There were no significant differences in4groups (P>0.05), and the IL-6/IL-10ratio in treatment groups were significantly different than that in control group (F=12.489,P=0.000) before treatment. After treatment, the IL-6/IL-10ratio raised remarkably in the80-89%group (P<0.05), while decreased significantly in90-110%treatment group (P<0.05).
3.4IL-10/TNF-α ratio:
There were no significant differences in4groups, and the IL-6/IL-10ratio in treatment group were significantly different than that in control group (F=57.084, P=0.000) before and after treatment. It raised remarkably in the control group(t=-4.746,P=0.01), while kept similar in other4treatment groups (P>0.05).
3.5Correlation analysis of inflammatory cytokine levels:
Prior to the treatment, the inflammatory cytokine's level was positively correlated with APACHE Ⅱ score (P<0.000); and anti-inflammatory cytokine was negatively correlated with APACHEII score (P=0.009and P=0.000,respectively). Post nutritional support treatment, IL-6levels were negatively correlated with actual energy supply (P=0.041); while IL-10, IL-4and TNF-a levels were not (P>0.05).
Conclusion:
1. Trauma and sepsis patients experience different resting metabolic disorder at early stage, the formulas on calculating resting metabolic rate have certain bias from measured values. Under the clinical acceptable criteria, no consistency between measured value and formula calculated ones were unsatisfactory. The formula calculated value will result in over or underfeeding.
2. Resting metabolic rate is negatively correlated to the nutritional condition admitted to the hospital, and is positively correlated to weight and BMI index.
3. Different degrees of nutritional support have no impact on28days prognosis, while providing90-110%of the required caloric value will improve the survival rate at day60. And different degrees of nutritional support have no impact on patients' mechanical ventilation duration, ICU stay or total hospital stay, but it affects ventilation-free time at28day. Providing90-110%of the required caloric value prolongs ventilation-free time at28day.
4. Appropriate nutritional support could restore the pro-inflammatory/anti-inflammatory balance through reducing pro-inflammatory cytokines release, and have no effect on pro and anti-inflammation balance.
营养支持是救治创伤、脓毒症患者的重要手段之一。但由于创伤、脓毒症病情复杂常使营养支持的实施结果并不理想。在ICU仍高达40%的患者发生营养不良。而造成营养不良的原因与不恰当的能量供应有着密切的关系。无论营养过度或营养不足均可使住院时间延长,机械通气时间延长,并发症增多。营养不足可使机体免疫功能低下,伤口愈合减慢、易发生院内感染；而营养过度使机体脏器负担加重,脂肪在肝脏的堆积,易出现高脂血症、高血糖及低磷酸血症,从而使免疫功能受损。而恰当的营养支持可以改善预后,提高机体免疫力,减少并发症。同时,机体在创伤、脓毒症的发生、发展过程中常伴随着一系列细胞因子、炎性介质的大量释放,表现为氧耗量增加、蛋白分解增强、心输出量增多、糖皮质激素增加、儿茶酚胺增加,这些代谢的改变受细胞因子的调节,并与预后及疾病严重程度相关。此时患者对营养物质的利用及合成也发生改变,在应激状态下如何进行恰当的营养支持,仍是一个临床尚没能很好解决的问题。造成这样的原因与临床上对于患者目标能量的制定仍无统一的标准有一定的关系,不恰当的能量供给可造成营养过度或营养不足,因此,制定一个适合患者的目标能量值就显得非常重要。
对于危重症营养支持中目标能量的确定,欧洲(ESPEN)及美国(ASPEN)肠外肠内协会推荐的既有以测量静息能量代谢值(MREE)为目标能量值,又有以体重或预计能量代谢公式计算值为目标能量,表明目标能量的确定仍存在不一致的观点,并且有关目标能量确定的指南推荐以专家共识为主,缺乏循证医学支持。
静息能量代谢测定的方法有直接测定法及间接测定法,其中,呼吸间接测热法(indirect calorimetry, IC)是临床上较常用的方法,它是根据能量守恒定理和化学反应的等比定律来监测能量代谢。人体在消耗碳水化合物、脂肪、蛋白质会产生热量,在提供能量的同时,也相应地消耗一定量的氧气并产生一定量的二氧化碳。根据此原理,测量一定时间内氧气的消耗量(VO2)及二氧化碳的产生量(VCO2),可根据Weir公式计算出这一时间内的能量消耗,推算出24小时内静息能量消耗。目前认为,间接测热法是测量静息能量代谢的金标准。虽然在临床上可实现静息能量代谢的监测,但测定的静息能量代谢值如何指导临床营养支持的应用以及其测量值是否可做为目标能量提供热卡,目前在国内外并无类似的研究及确切的结果。
目的：
主要目的：观察以不同目标能量值提供能量对预后的影响。监测静息能量代谢变化,并根据静息能量代谢值提供不同层次的能量供给,观察不同水平热卡的能量供给对创伤、脓毒症28天、60天死亡率的影响,观察哪种能量供给方案更适合危重病目标营养的制定,提出更为确切的方案,从而指导临床营养的实施。
次要目的：
1、观察创伤、脓毒症静息能量代谢特点及与预计公式之间的一致性分析及对预计公式与静息能量代谢进行相关性分析。
2、观察不同热卡的能量供给对创伤、脓毒症机械通气时间、免机械通气时间的影响。
3、观察不同热卡的能量供给对创伤、脓毒症营养指标、肝功能、免疫功能、炎性因子的影响。
方法：
第一部分创伤、脓毒症患者静息能量代谢的特点、监测与评估
选择2011年6月1日至2013年12月31日期间广州军区陆军总医院重症医学科及武警广东总队医院重症监护科收治的脓毒症、创伤(包括手术后)病人。记录患者入住ICU后基本病情资料,测量其静息能量代谢值,并利用各种公式(H-B公式、H-B×1.2公式、ACCP公式、Ireton-Jones92公式、Ireton-Jones97公式、Mifflin公式)推算出预计的能量代谢值。对公式预计值与静息能量代谢实测值进行偏倚性分析；分析各种公式预计值准确性；分析创伤、脓毒症患者静息能量代谢早期分布状态；对公式预计的能量代谢值与实测的静息能量代谢值进行一致性分析,评估临床可接受范围内的公式准确率；对静息能量代谢实测值与公式预计值进行相关性分析。
第二部分不同目标能量值提供能量对创伤、脓毒症患者预后及并发症的影响
选择2011年6月1日至2013年12月31日期间广州军区陆军总医院重症医学科及武警广东总队医院重症监护科收治的脓毒症、创伤(包括手术后)病人。其中对253例进行了研究。根据随机分组表分为4组,其中1组为以ACCP公式25kcal/kg/天为目标能量值；2组为以静息能量代谢值的80-89%为目标能量值；3组为静息能量代谢值的90-110%为目标能量值；4组为静息能量值110%以上为目标能量值。所有脓毒症患者在入ICU后均接受原发病常规治疗。病情平稳后24小时内行肠内营养支持治疗(EN),目标能量值达标时间为4-5天,如未达标则予以肠外营养(PN)补充。蛋白给予量为1.0g/kg/d。记录每日给予能量的量、途径、蛋白给予量、开始喂养时间,记录每周累积能量平衡及转出ICU或出院(死亡)时累积能量平衡；记录患者在ICU停留时间及住院时间、28天无需机械通气时间、28天、60天死亡率,进行60天生存分析；记录患者治疗前(day0)、治疗后第一天(day1)、治疗后第三天(day3)、治疗后第五天(day5)、治疗后第七天(day7)或转科、死亡时(discharge)的APACHE II评分、SOFA评分；测量患者在营养治疗前(day0)、治疗后第七天(day7)、第十天(day10)、第十四天(day14)的前白蛋白、视黄醇结合蛋白、转铁蛋白水平、肝功能指标；监测患者在营养治疗前(day0)、治疗后第七天(day7)免疫因子(CD14+/HLA-DR)表达的改变。
第三部分不同目标能量值提供能量对创伤、脓毒症患者炎性因子水平的影响
选择2011年6月1日至2013年12月31日期间广州军区陆军总医院重症医学科及武警广东总队医院重症监护科收治的脓毒症、创伤(包括手术后)病人共有45例患者纳入研究。按前期分四组及对照组。对照组为同期入院患者,非脓毒症外科患者(APACHEII评分低于12分)。记录病情指标,记录检测患者在营养治疗前(day0)、治疗后第七天(day7)血清炎性因子的变化(IL-6、IL-10、 TNF-α、IL-4)。记录促炎/抗炎反应平衡的变化(IL-6/IL-10、IL-10/TNF-α)。
结果：
1创伤、脓毒症患者静息能量代谢的特点、监测与评估
1.1静息能量代谢实测值与各种预计公式计算值对比
ACCP法估计的能量代谢值与间接测热法测得的实测值比较无偏倚,评估准确率略高,差异无统计学意义(t=1.534, P=0.126)。而其他公式预计值与实测值比较差异有统计学意义,其中Ireton-Jones92估计值最高,与实测值比较差异有统计学意义(t=12.114, P=0.000); H-B公式、Mifflin公式所估计的能量代谢值均低于实测值,与实测值比较差异有统计学意义(t分别为6.478、7.938,P均<0.001)；Ireton-Jones97公式与H-B×1.2系数公式评估值分别与实测值比较,差异有统计学意义(t值分别为4.909、2.657,P值分别为0.000、0.008)。
1.2创伤、脓毒症静息代谢特点
创伤、脓毒症患者有50%以上处于高代谢状态,而正常代谢范围在22.22%-22.83%,低代谢状态为22.73%-27.78%,三组间比较无显著性差异(χ2=0.706,P=0.951)。
1.3各种公式与实测值之间一致性分析：
大多数公式在95%界限范围内的一致性较高,均为95%以上,其中ACCP公式、Ireton-Jones92公式一致性达97%以上,但一致性界限范围过大,为临床上不能接受范围,而±10%MREE (-195.46,195.46) kcal/day为临床可接受范围,在此范围内再进行一致性分析,各公式的一致性符合率明显下降,ACCP公式、H-B公式及Mifflin公式一致性分别为27.27%、27.67%、27.67%,而Ireton-Jones92公式一致性为18.18%。
1.4实测值相关性分析
各种公式预计值与实测值均存在相关性,差异有统计学意义,但相关关系并不密切。其中Mifflin相关性略强,r值为0.474,而ACCP公式相关性较低,r值为0.317,P均<0.001。而静息能量代谢与体重、BMI值呈正相关,r、P分别为0.388、0.000及0.238、0.008；与NRS2002负相关,r=-0.143,P=0.023；与APACHE II无相关性,P值=0.511。
2不同目标能量值提供能量对创伤、脓毒症患者预后及并发症的影响
2.1各组热卡值及蛋白摄入比较
各组第一周摄入热卡数比较,差异有统计学意义(F=16.366,P=0.000),组间多重比较显示80-89%组第一周平均摄入能量、第一周累积摄入、平衡住院期间摄入能量平衡均明显低于其他三组,四组之间第一周平均蛋白摄入比较,差异无统计学意义(F=2.028,P=0.110)。
2.2不同目标能量组提供能量对在ICU停留时间、机械通气时间的影响
不同目标能量组对机械通气时间、ICU停留时间、住院时间,差异无统计学意义(F值分别为0.543,0.896,1.481,P值分别为0.654、0.445、0.220),而28天内免机械通气时间差异有统计学意义(F=2.763,P=0.043),其中90-110%、25kcal/kg组免机械通气时间较另两组长,组间多重比较差异有统计学意义(P<0.05)。
2.3不同目标能量组28天死亡率、60天死亡率的比较
90-110%组28天死亡率12.1%,低于另三组,其余各组死亡率为23.3%以上,但各组28天死亡率比较,差异无统计学意义(χ2=6.685,P=0.083)。60天死亡率分析结果显示所有各组死亡率均上升,其中,90-110%组其死亡率上升至21.5%,而另外三组则升至40%以上,各组比较差异有统计学意义(χ2=12.712,P=--0.005)。
2.460天Kaplan-Meier生存分析：
经Kaplan-Meier法进行60天生存分析：结果显示90-110%组累积生存率高于其他三组,差异有统计学意义(χ2=10.375,P=0.016)。
2.5治疗前后营养指标的变化：
随着时间的推移,视黄醇结合蛋白逐步升高,不同时间点之间有显著性差异(F=I0.126,P=0.000),其中>110%组在第十四天达到最高值。转铁蛋白在营养治疗前后不同时间之间有显著性差异(F=4.611,P=0.016),前白蛋白也随着时间的推移而逐渐上升,与营养开始前比较,差异均有统计学意义(F=3.602,P=0.031)。
2.6治疗前后免疫功能的变化：
在一周内营养支持后各组CD14+/HLA-DR的表达无明显变化,差异无统计学意义(F=1.992,P=0.166),治疗一周后各组之间比较,差异有统计学意义(F=3.739,P=0.016),其中80-89%组、90-110%均有不同程度的上升(P<0.05)。从不同营养支持途径分析,CD14+/HLA-DR表达在营养治疗前后无不明显变化,而给予肠内营养、肠内营养与肠外营养联合应用的患者CD14+/HLA-DR表达增加,肠外营养途径的CD14+/HLA-DR表达下降,三组比较差异有统计学意义(F=6.612,P=0.003)。
3不同目标能量值提供能量对创伤、脓毒症患者血清炎性因子水平的影响
3.1血清炎性因子的变化：
IL-4、IL-10、TNF-α:实验组与对照组比较差异有统计学意义(F值分别为8.684、11.974、348.77,P值均小于0.001)。IL-6：各组比较差异无统计学意义(F=0.689,P=0.598)。各实验组组间比较,差异无统计学意义(P>0.05)。其中TNF-α:实验组80-89%组与25kcal/kg组、>110%组比较差异有统计学意义(P均<0.05)：80-89%组与90-110%组比较,差异无统计学意义(P均>0.05)。
3.2各实验组营养治疗前后炎性因子的变化
IL-6：90-110%组营养支持治疗后IL-6水平下降,与治疗前比较差异有统计学意义(t=3.779,P=0.005),其余各组治疗前后差异无统计学意义(t值分别为1.606、-0.482、1.918,P值分别为0.147、0.643、0.091)。TNF-a:各组治疗前后比较差异无统计学意义(t值分别为1.296、-1.342、-0.199、-0.249,P分别为0.231、0.216、0.847、.0.810)。IL-4：25kcal/kg组、>110%组营养治疗前后对比差异无统计学意义(t值分别为0.337、-2.133,P值分别为0.745、0.065)；80-90%组、90-110%组营养治疗前后对比差异有统计学意义(t值分别为-2.730、-11.801,P值分别为0.026、0.000)。IL-10：各组营养治疗前后对比差异无统计学意义(t值分别为0.357、1.252、-0.292、0.605,P值分别为0.730、0.246、0.778、0.562)。3.3IL-6/IL-10的变化
治疗前各实验组与对照组比较差异有统计意义(F=12.489,P=0.000),多重比较,结果显示各实验组与对照组组间差异有统计学意义(P<0.05),各实验组之间差异无统计学意义(P>0.05)。治疗后不同组之间有显著性差异(F=11.843,P==0.000),其中实验各组与对照组,差异有统计学意义(P<0.05),其他实验各组差异无统计学意义(P>0.05)。各组治疗前后对比90-110%下降,与治疗前比较差异有统计学意义(t=4.007,P=0.004)。
3.4IL-10/TNF-a的变化
营养治疗后不同组间有差异(F=57.084,P=0.000),其中各实验组之间差异无统计学意义(P>0.05),而与对照组比较有显著性差异(P<0.05)。对照组营养治疗前后IL-10/TNF-α值比较差异有统计学意义(t=4.746,P=0.01),而其他实验组营养治疗前后对比无明显统计学差异(t值分别为0.803、0.541、-0.905、-0.599,P值分别为0.445、0.509、0.392、0.566)。
3.5炎性因子的相关性研究：
营养治疗前TNF-a、IL-6水平与APACHE II评分呈正相关(P均<0.001)；IL-4、IL-10与APACHE II评分呈负相关(P=0.009,P=0.000)。营养治疗后IL-6水平与实际供能呈负相关(P=0.041)；IL-10、IL-4及TNF-a与实际供能无相关性(P=0.332,P==0.098,P=0.230)。
结论
1创伤、脓毒症患者静息能量代谢早期紊乱,所有预计能量代谢公式均不能反映实际静息能量代谢状态,在临床可接受范围内的一致性更低,以公式预计值提供能量可能造成营养不足或营养过剩。
2以不同目标能量提供给能量短期内对患者预后影响不明显(28天),但对60天可产生影响,其中以静息能量代谢实测值90-110%的热卡供能可改善60天生存。不同目标能量的供给对患者机械通气时间、ICU停留时间及住院时间无影响,但对28天内免机械通气时间有影响,其中,给予静息能量代谢实测值90-110%的热卡可延长免机械通气时间。
3经过营养支持后所有能量支持组营养指标在10天后均有所改善,营养支持短期内对免疫功能无明显影响,但给予肠内营养及90-110%能量组CD14+/HLA-DR表达较其他组增加。
4促炎因子IL-6与能量供给呈正相关,适当的营养支持治疗可能可以通过减少部分促炎因子的释放来协助促炎/抗炎因子平衡,而短期的营养支持对抗炎/促炎平衡无明显调理作用。
Background:
Nutritional support is an important method in the treatment of trauma and sepsis patients. However, implementation of nutritional support often results in no satisfactory results due to its complicated co-morbility. Up to40%of ICU patients experience various degrees of malnutrition. The cause of malnutrition is closely related to inadequate energy supply. Both nutrition underfeeding and overfeeding could result in malnutrition. Underfeeding could lower immunological function, prolong wound recovery and increase nosocomial infectious morbidity; while overfeeding aggravates the burdens of organ, and increases the likelihood of steatosis, hyperlipidemia, hyperglycemia, low hypophosphatemia, and impairs immune function. Either underfeeding or overfeeding could prolong hospitalization, mechanical ventilation duration and raise associated complications. Appropriate nutritional support can improve prognosis, immunity, and reduce complications. But how to provide proper nutritional support is a debated issue which still lacks effective clinical standard. The lacking of clinically developed uniform standards to optimize patient's nutritional state contributes to malnutrition. Therefore, setting an optimal nutrition standard for patients is vital.
Indirect calorimetry (IC) is based on the energy conservation law of geometric theorems and monitor chemical reactions in energy metabolism. Through the consumption of carbohydrates, fat and proteins, the human body will produce heat, consume a certain amount of oxygen and produce a certain amount of carbon dioxide. According to this principle, by measuring the consumption of oxygen (VO2) and the release of carbon dioxide (CO2) in a preset time, with the Weir equation, the energy consumption could be calculated and the energy consumption of24hours could be speculated. To date, IC is considered as the golden standard in measuring resting energy expenditure, however, the application of IC in determining the optimal nutrition standard still lacks global similar prospective randomized controlled trials with positive results to support the hypothesis to use resting energy expenditure to determine the target energy.
With regards to setting optimal nutritional standard for critically ill patients, Europe (ESPEN) and the U.S.(ASPEN) guidelines recommend measuring resting energy expenditure (MREE) to derive the optimal nutritional state, and also using weight and energy metabolism estimation formula to calculate the target energy state, these recommended approaches relies mainly on the consensus of experts, supported by the lack of evidence-based
During and post trauma and sepsis, the human body will release a series of cytokines, and also experience in different degrees of increase in terms of oxygen consumption, Proteolysis, Cardiac output, Glucocorticoid and Catecholamine. The Utilization and synthesis of nutrients also changed, the traditional nutritional support could not offset the increase in catabolism and protein loss. Some cytokines such as TNF-a, IL-2, IL-6involved in the regulation of inflammatory reactions, the IL-6protein will induce the liver to prioritize the synthesis of Acute phase proteins (such as the C-reactive protein), thus Albumin, Pre-albumin, Transferrin and Immunoglobulin concentration decreases. The change of Pro-inflammatory cytokines and lower metabolism are associated with mortality.
Objective:
Primary endpoints:To observe the effect of different target energy value on prognosis. IC was utilized to measure changes in resting metabolic rate to provide different levels of energy supply. The effect of different caloric supply on28day,60day mortality rate of trauma and sepsis patients was observed. Which level of caloric supply is the most suitable for Critical patients were analyzed, so as to provide a more accurate strategy to instruct the clinical nutritional support implementation.
Secondary endpoints:
1. To observe the resting energy expenditure characteristic related to trauma, sepsis patients, to perform the consistency analysis between our value and predicted formula and to discuss the related factors of resting metabolic rate.
2. To observe the impact of different caloric supplement levels on the mechanical ventilation and ventilation-free days of trauma and sepsis patients.
3. To observe the impact of different caloric supplement levels on the nutritional indicators, liver function, inflammatory indicators, immune function and inflammatory cytokines in trauma and sepsis patients.
Methods:
Part1:The characteristic, monitoring and evaluation of resting energy metabolism in trauma and sepsis patients.
Patients with sepsis and trauma (including post-surgery) were included from2011/6/1to2013/12/31admitted to the ICU of Guangdong Armed policed Hospital. The characteristics of patients were recorded and the resting metabolic energy value was measured. The values of resting energy metabolism in various formulas were calculated. The bias analysis between the measured resting energy metabolism value and calculated formula value were performed and the accuracy was compared; the energy distribution were analyzed and the consistency analysis between formula estimation data and the actual measuring value of the metabolic energy level were processed to evaluate the clinical acceptable ranges. The correlation analysis between the two approaches were also conducted.
Part2:The impact on the outcome and complications under different target energy level in trauma and sepsis patients.
253cases of patients admitted to the ICU of Guangdong Armed policed Hospital were included from2011/6/1to2013/12/31and divided into four groups through randomization:group one used the ACCP formula of25kcal/kg/day as the target energy level; group two used the80-89%of the target energy level from the resting metabolic rate; group three using90-110%as target; group four using over110%. All patients were received conventional treatment, and enteral nutritional supports were administered within24hours under stable condition.4-5days were cost to achieve the target energy level, and if not, parenteral nutritional support was supplemented. Protein dosage is1.0g/kg/day. Daily support of energy level, protein level and administration method were recorded, along with administration time, accumulated energy balance weekly and the total energy balance when transferred out of ICU or out the hospital (deceased). The mortality rate on28day and60day, ICU stayed and total hospital stay, ventilation-free days within28day were recorded, and survival analysis of60day was performed. the APACHE II, SOFA score before treatment (day0), first day under treatment (day1), third day under treatment (day3), fifth day under treatment (day5), seventh day under treatment (day7) or after transfer out or discharge were calculated, and the pre-albumin, retinol binding protein, transferrin, liver function index level were detected before treatment (day0), seventh day under treatment (day7), tenth day under treatment (day10), fourteenth day under treatment (day14). Gauge the immune index(CD14+/HLA-DR) on before treatment (day0) and seventh day under treatment (day7).
Part3:The impact of different target energy level on the inflammatory cytokine levels in trauma and sepsis patients.
45cases of patients admitted to the ICU of Guangdong Armed police Hospital were included from2011/6/1to2013/12/31and were divided into the same four groups plus control group. The patients who enrolled in the control group were hospitalized during the same period without sepsis (APACHE II score<12). The characteristics were recorded, and the inflammatory cytokine levels (IL-6、IL-10、 TNF-α、IL-4) were measured on the day before nutritional support (day0) and seventh day under treatment (day7). The Pro-inflammatory/Anti-inflammatory balance (IL-6/IL-10、IL-10/TNF-a) was observed.
Result:
1. The characteristics, monitoring and assessment of resting energy metabolism in trauma and sepsis patient:
1.1Comparison of measured resting energy metabolism values with other calculated formula values:
The resting energy metabolism rate estimated by ACCP was not significantly different compared with indirect measuring values (t=1.534, P=0.126). Where other calculated formula values was significantly different(t=6.478、7.938, respectively and P<0.000) from indirect measuring value.
1.2. The characteristic of resting energy metabolism:
More than50%of trauma and sepsis patient manifested a hypermetabolic state, with22.22%-22.83%manifesting normal and the rest manifesting hypo-state. There was no significant difference among three groups (P>0.05).
1.3. The correlations between indirect measurement and different calculated formula values:
The majority of the calculated formula values had up to95%precision consistency in95%ranges, while ACCP and Ireton-Jones92formula indicated more than97%precision consistency. Due to the fact that large range outside the clinical acceptance, and±10%MREE (-195.46,195.46) kcal/day is more reasonable range, consistency analysis was re-performed, and the previous high precision were significant decreased with ACCP, H-B and Mifflin formula consistency of27.27%,27.67%and27.67%, respectively, and Ireton-Jones92consistency of18.18%.
1.4Direct measurement correlation analysis:
There was a significant correlation between various formula values and the direct measurement value (P<0.000), with Mifflin with r value of0.474to be strongest correlated and ACCP with r value at0.317to be weaker. While resting energy metabolism were positively correlated with body weight and BMI, and negatively correlated with NRS2002, and no correlation with APACHE II were observed (P=0.511).
2. The effect of different target energy levels on the prognosis and complications in sepsis and trauma patients.
2.1The comparison of calorie and protein intake:
There is a statistical significance in the initial week calorie intake in all groups (F=16.366,P=0.000).The average energy intake, the accumulative energy intake balance and the total energy balance during first week were much lower in group2than those of other three groups, while the average protein intake between the four groups during the first week were similar (F=2.028,P=0.110).
2.2Various target energy on ICU stay and mechanical ventilation duration:
There were no statistical significances of mechanical ventilation duration, ICU stay and total hospital stay in all groups (F value is0.543,0.896,1.481,P value is0.654,0.445,0.220,respectively), except for ventilation-free time within28day (F=2.763, P=0.043). The ventilation-free time within28day were much longer in90-110%and25kcal/kg group compare with the other two groups.
2.3Comparison of the28-day,60-day mortality rate.
The28-day mortality rate of the90-110%group (12.1%) was lower than the other three groups (>23.3%) with no significance. The60day mortality rate all increased, with90-110%group of21.5%and other three groups of more than40%, and the compassion was statistically significant (χ2=12.712,P=0.005).
2.460-Day Kaplan-Meier Survivability Analysis:
The60Day Kaplan-Meier analysis showed that the mortality rate was lower in90-110%group than those in other three groups, with statistical significance (χ2=10.375,P=0.016).
2.5The changes of nutritional indexes pre and post treatment:
With the pass of time, the level of Retinol binding protein raised gradually and significantly (F=10.126,P=0.000). The rise in80-89%group was not significant, while the other three groups observed remarkable increase. Transferrin and pre-albumin also rised significantly over time (F=4.611,P=0.016). While there was no difference among the4groups (F=0.411,P=0.868).
2.6The changes in immune functions pre and post treatment:
The CD14+/HLA-DR expressions in all groups were similar in first week (F=1.992, P=0.166) and increased significantly since second week (F=3.739,P=0.016) with the80-89%and90-110%group to be more distinct. Through analyzing the different nutritional support approaches, the CD14+/HLA-DR expressions in all groups changed little in first week, after one week of the treatment, the HLA-DR presentation was increased in EN group and mixed group combining EN and PN, while decreased in PN group, and the difference were statistically significant (F=6.612,P=0.003).
3. The impact of different target energy level on inflammatory cytokines levels in sepsis and trauma patients.
3.1The cytokine levels after treatment:
There were significant differences in IL-4and IL-10levels after treatment across the groups (F=6.766,P=0.000,and F=4.479,P=0.004). The IL-4levels in80-89%group were much different from those in90-110%group and25kcal/kg group (P<0.05), and those in>110%group were significantly different from25kcal/kg group and90-110%group (P<0.05). There was no difference in IL-4levels in90-110%group and25kcal/kg group (P>0.05). The IL-10levels were similar in4groups (P>0.05) and higher than that in control group (P>0.05). The IL-6and TNF-a levels were similar in all groups (F=0.617,P=0.653vs F=2.363, P=0.070).
3.2The inflammatory cytokine levels after treatment:
The IL-6levels in90-110%group decreased after treatment (t=3.779,P=0.005), while other groups observed non statistical significances (P>0.05). The TNF-a and TL-10levels were similar in all groups (P>0.05). The IL-4levels only in80-89%group and90-110%group changed significantly (P<0.05).
3.3IL-6/IL-10ratio:
There were no significant differences in4groups (P>0.05), and the IL-6/IL-10ratio in treatment groups were significantly different than that in control group (F=12.489,P=0.000) before treatment. After treatment, the IL-6/IL-10ratio raised remarkably in the80-89%group (P<0.05), while decreased significantly in90-110%treatment group (P<0.05).
3.4IL-10/TNF-α ratio:
There were no significant differences in4groups, and the IL-6/IL-10ratio in treatment group were significantly different than that in control group (F=57.084, P=0.000) before and after treatment. It raised remarkably in the control group(t=-4.746,P=0.01), while kept similar in other4treatment groups (P>0.05).
3.5Correlation analysis of inflammatory cytokine levels:
Prior to the treatment, the inflammatory cytokine's level was positively correlated with APACHE Ⅱ score (P<0.000); and anti-inflammatory cytokine was negatively correlated with APACHEII score (P=0.009and P=0.000,respectively). Post nutritional support treatment, IL-6levels were negatively correlated with actual energy supply (P=0.041); while IL-10, IL-4and TNF-a levels were not (P>0.05).
Conclusion:
1. Trauma and sepsis patients experience different resting metabolic disorder at early stage, the formulas on calculating resting metabolic rate have certain bias from measured values. Under the clinical acceptable criteria, no consistency between measured value and formula calculated ones were unsatisfactory. The formula calculated value will result in over or underfeeding.
2. Resting metabolic rate is negatively correlated to the nutritional condition admitted to the hospital, and is positively correlated to weight and BMI index.
3. Different degrees of nutritional support have no impact on28days prognosis, while providing90-110%of the required caloric value will improve the survival rate at day60. And different degrees of nutritional support have no impact on patients' mechanical ventilation duration, ICU stay or total hospital stay, but it affects ventilation-free time at28day. Providing90-110%of the required caloric value prolongs ventilation-free time at28day.
4. Appropriate nutritional support could restore the pro-inflammatory/anti-inflammatory balance through reducing pro-inflammatory cytokines release, and have no effect on pro and anti-inflammation balance.
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