ICM译文：重症患者的开放与限制性液体治疗

今天读到一篇Intensive care medicine的短评，对于重症患者补液的认识有一些值得玩味的，因此推荐给大家。

总结而言，文中主要是说：补液应根据液体反应性，并实施限液+早期缩血管药物+“脱复苏”策略。其中还提到不要以为限液就是单纯减少用于补液的液体，诸如药物稀释剂和营养中的液体不容忽视——这些“液体切换”占所有液体摄入量的33％！......

Liberal versus restrictive fluid therapy in critically ill patients 

重症患者开放与限制性的液体治疗

Silversides, J.A., Perner, A. & Malbrain, M.L.N.G. Intensive Care Med (2019). 

https:///10.1007/s00134-019-05713-y

静脉输液的是重症监护中最常用的治疗方法之一，已从补充腹泻丢失的水和电解质演变为“优化”心输出量的概念。不过它常被错误地认为是（优化）组织灌注。 由于重症监护已从历史上注重生理指标正常化转为严格应用基于证据的实践以产生最佳的远期结局，因此重新评估基础治疗（如静脉输液）的作用是十分必要。

Administration of intravenous fluid is one of the most commonly applied therapies in critical care, and has evolved from the replacement of water and electrolytes lost in diarrhoeal illness to the concept of ‘optimising’ cardiac output and thus, it is often incorrectly assumed as tissue perfusion [1]. As critical care transitions from a historical focus on normalisation of physiology towards the rigorous application of evidence-based practices which result in the best possible long-term outcomes, a re-evaluation of the role of basic therapies, such as intravenous fluids, is necessary.

休克通常被分为低血容量（例如，出血性）、分布性（例如，败血症）、阻塞性、心源性或神经源性，并互有重叠。应仔细考虑ICU中异常血流动力学的病因，并针对可能的原因进行特定治疗；特别重要的是，相关的低灌注存在与否，不过根据我们的经验，实践中常常并非如此。由于低血容量是最易引起休克的可逆原因，因此初始治疗“开放性”使用液体静脉推注作为应对各种血液动力学情况（包括低血压、心动过速、少尿、大理石皮纹和血乳酸升高）十分常见[2 ，3]。这种做法与国际指南规定脓毒症初始治疗相符[4]，并在整个危重病期间贯彻进行，往往没有仔细考虑其可能的益处与有害后果[2]。

Shock is typically described as hypovolaemic (e.g., haemorrhagic), distributive (e.g., septic), obstructive, cardiogenic, or neurogenic in origin, with frequent overlap. While careful consideration should be given to the aetiology of abnormal haemodynamics in the ICU with specific treatment directed at likely causes and, crucially, on the presence or absence of associated hypoperfusion, in our experience this is often not the case in practice. As hypovolaemia is the most readily reversible cause of shock, a ‘liberal’ approach using intravenous fluid boluses as the initial response to a variety of haemodynamic situations, including hypotension, tachycardia, oliguria, skin mottling, and elevated serum lactate levels is common [2, 3]. This approach is consistent with international guidelines for the initial management of sepsis [4], and is often continued throughout the duration of critical illness, often without careful consideration of likely benefits versus harmful consequences [2].

Efficacy of intravenous fluid administration 静脉补液的作用

虽然出现在急诊室（ED）的患者可能是严重的低血容量并且最初对静脉注射液有反应，但效果随着时间的推移会迅速减少。在最近一项关于脓毒症乳酸与外周灌注指标对比引导液体复苏的随机试验中，不到5％的患者在起病后8小时出现液体反应（图1）[5]。直接从ED入住ICU的患者也是这种情况，当患者到达ICU时也没有液体反应——因此，流体反应可能是例外而不是规则。实际上，ICU中给予的流体推注的生理效应似乎很小。在ARDS [6]和脓毒症[7]的随机试验的事后分析中，液体推注后血压的平均升高大约为2 mmHg，心率降低1 bpm，尿量没有变化，甚至这些适度的好处通常会在短短1小时后消失[8]。这些数据与临床医生报告的能感知到近70％流体推注的疗效形成鲜明对比[2]。

While patients presenting to an emergency department (ED) may be profoundly hypovolaemic and initially respond to intravenous fluid, the effects diminish rapidly over time. In a recent randomised trial of lactate versus peripheral perfusion-guided fluid resuscitation in sepsis, less than 5% of patients were fluid responsive at 8 h from presentation (Fig. 1) [5]. This is also the case in patients admitted directly from the ED to ICU, by the time patients reach the ICU, therefore, fluid responsiveness is perhaps the exception rather than the rule. Indeed, the physiological effects of fluid boluses given in ICU appear to be small. In post hoc analyses of randomised trials in ARDS [6] and sepsis [7], the mean increase in blood pressure following a fluid bolus was in the order of 2 mmHg and decrease in heart rate 1 bpm, with no change in urine output, and even these modest benefits often dissipate after as little as 1 h [8]. These data are in stark contrast to clinician-reported perceptions of efficacy in nearly 70% of fluid boluses [2].

Potential harm from fluid administration静脉输液的有害作用

在大量液体摄入的情况下，伴随着减少水盐排泄的内分泌和肾脏反应，液体和钠积聚造成的水盐正平衡十分常见。而重症患者的液体积聚始终与不良后果相关，这一点已在患有败血症、ARDS [9]和急性肾损伤（AKI）[10]的成人和儿童以及更广泛的危重病群中证实[11]。剩下的问题是这是否代表因果关系，或仅仅是因为适应证混淆，而使更严重的患者更可能接受较大量的液体且不太可能采取措施来限制这种液体积聚。另一个问题是，如果存在危害，是由于给药还是由于液体和钠的积累，而实验数据提示可能均有涉及[12]。快速液体推注的潜在危害机制包括内皮糖萼的剪切损伤、血管内空间维持液体的脆弱屏障、血管舒张和肾上腺素能反应降低[13]，而液体积聚可能导致血液稀释，静脉升高压力导致灌注压力梯度降低，间质水肿导致毛细血管和细胞之间的氧扩散受到抑制[14]。

In this context of large volume fluid intake, together with endocrine and renal responses which predispose to reduced water and salt excretion, the accumulation of a positive fluid and sodium balance is common. Fluid accumulation in critically ill patients is consistently associated with adverse outcomes. This has now been demonstrated in adults and children with sepsis, ARDS [9], and acute kidney injury (AKI) [10], as well as broader cohorts of critical illness [11]. The residual question is whether this represents a causal relationship, or merely confounding by indication, with more severely unwell patients being more likely to receive larger volumes of fluid and less likely to undergo measures to limit this fluid accumulation. A further question is whether the harm, if it exists, is due to the administration or to the accumulation of fluid and sodium, since experimental data implicate both [12]. Potential mechanisms of harm from rapid fluid boluses include shearing injury to the endothelial glycocalyx, the fragile barrier by which fluid is maintained within the intravascular space, vasodilation, and decreased adrenergic responsiveness [13], while accumulation of fluid may result in haemodilution, elevated venous pressure with resultant decrease in perfusion pressure gradients, and interstitial oedema with resultant inhibition of oxygen diffusion between capillaries and cells [14].

一般而言，可以使用两种互补的方法来预防和治疗流体过载：限制性流体给药，以及主动去除积聚的流体。初始复苏和随后液体排出的不同阶段可以用ROSE模型（ESM 1）[1]进行了说明和解释。

Broadly speaking, two complementary approaches may be used in the prevention and treatment of fluid overload: restrictive fluid administration, and the active removal of accumulated fluid. The different phases following initial resuscitation and subsequent fluid removal are illustrated and explained in the ROSE model (ESM 1) [1].

Restrictive fluid administration 限液

确定“流体反应性”的预测指标受到相当的关注，即生理或超声心动图参数，如每搏输出量变化[3]、被动抬腿试验[15]，或速度时间积分[16]，以预测输注液体是否会 产生血液动力学变量的改善。这些预测因子的一个基本原则就是补液只能限制于至少可能获益的情况下。

Considerable emphasis has been placed on identifying predictors of ‘fluid responsiveness’, i.e., physiological or echocardiographic parameters such as stroke volume variation [3] passive leg raise manoeuvres [15], or velocity time integral [16] to predict whether a fluid bolus will produce some improvement in haemodynamic variables. One rationale for these predictors is to limit fluid administration to situations where there is at least a possibility of clinical benefit.

虽然直观上将流体反应性预测因子纳入整体血液动力学的评估貌似合理，但即使使用正确，固有问题仍然存在。首先，补液直至达到无液体反应状态这一做法从未显示出对脓毒症患者有益。其次，每个预测因子都有显著不足，例如，在肺保护性通气、自主呼吸、心律失常、右心衰竭或腹内压升高的情况下，每搏输出量变异率就是无效的[3]。第三，即使液体反应性的预测是准确的，用于判断液体推注的“成功”或“失败”的措施是全局参数，例如血压和心输出量，而这些指标并不能很好地预测组织灌注，特别是在脓毒症中，大循环与微循环之间的一致性经常丢失[14]。

While incorporating predictors of fluid responsiveness into overall haemodynamic assessment seems intuitively reasonable, inherent problems remain even if used correctly. First, administering fluid until a fluid-unresponsive state is reached has never been shown to be of benefit in sepsis. Second, each of the predictors is subject to major limitations, for example, stroke volume variation is not useful in the context of lung-protective ventilation, spontaneous breathing, cardiac arrhythmias, right heart failure or increased intra-abdominal pressure [3]. Third, even if the prediction of fluid responsiveness is accurate, measures used to judge ‘success’ or ‘failure’ of a fluid bolus are global parameters such as blood pressure and cardiac output, which are poor predictors of tissue perfusion, particularly in sepsis where coherence between macro- and micro-circulation is frequently lost [14].

为了减少补液，早期可能需要使用缩血管剂。缩血管剂的早期应用有可能通过从静脉腔募集血液来减少血管内容量缺失，同时避免补液的不利影响[17]。另一方面，如延迟缩血管药物的使用，即直到液体复苏也无法纠正休克才启用缩血管药物可能会延迟疾病的解决，另有人认为假设液体复苏比使用缩血管药物更安全，这一假设与现有数据相悖[18,19]，可能部分受医疗资源限制的驱动。

To reduce fluid administration, the early use of vasopressors may be needed. Early application of vasopressors has the potential to reduce intravascular volume deficit by recruiting blood from the venous compartment, while avoiding the detrimental effects of fluid administration [17]. Delaying vasopressor use until fluid resuscitation has demonstrably failed to correct shock, on the other hand, may delay resolution, and assumes that fluid resuscitation is safer than vasopressor use, an assumption which is contrary to the available data [18, 19] and which may be driven in part by resource constraints.

Deresuscitation 脱复苏策略

若更严格地使用液体，并且在可能的情况下尽早使用缩血管药物，就可减少补液，但使用这种策略不可能完全避免液体过量。 ICU的液体摄入有各种来源，许多是强制性的，如药物稀释剂和营养。最近的一项研究表明，这种“液体切换”占所有液体摄入量的33％，而复苏液的比例只有7％[20]。除了限制复苏液外，避免液体超负荷可能需要“脱复苏策略”，其被定义为使用利尿剂或超滤[11]，这种方法可缩短机械通气和ICU停留的持续时间[9]。高渗白蛋白与利尿剂共同给药可促进血液动力学稳定和利尿[21,22]。

While more restrictive use of fluid, together with earlier use of vasopressors if needed, may reduce fluid administration, it is unlikely that fluid overload can be entirely avoided using this strategy. Fluid intake in ICU is from a range of sources, and many are obligatory such as drug diluents and nutrition. A recent study showed that this ‘fluid creep’ accounts for as much as 33% of all fluid intake compared to 7% for resuscitation fluids [20]. Besides restriction of resuscitation fluids, avoidance of fluid overload is likely to require deresuscitation, defined as active fluid removal using diuretics or ultrafiltration [11], an approach which shortens the duration of mechanical ventilation and ICU stay [9]. Co-administration of hyperoncotic albumin along with diuretics may promote haemodynamic stability and diuresis [21, 22].

正在进行的三个主要方面的工作集中在：（1）限制性液体复苏方法，包括在需要时尽早使用缩血管药，（2）使用脱复苏策略预防和治疗复苏后的液体积聚，以及（3）寻找可以预测患者是否能从补液中受益的工具。同时，临床医生应该设法避免在不太可能获益的情况下补液，相当于灌注充分但仍需要缩血管剂，或灌注不充分但无液体反应者。复苏后，使用利尿剂或超滤来减少体液过载似乎是安全的，可以加速从严重疾病中的恢复。这反映在流体管理的动态阶段（ROSE）中。最后，虽然这些代表了广泛适用的原则，但生理指标的监测或生物标记物的改进在未来可能会允许更加个性化的液体管理方法。与众所周知的抗生素阶梯管理概念类比，现在也该是对重症患者实施补液的阶梯管理的时代了，即液体也应被视为药物。

Ongoing work is focussed on three main areas: (1) restrictive approaches to fluid resuscitation, involving early use of vasopressors if needed, (2) the use of deresuscitative measures to prevent and treat fluid accumulation following resuscitation, and (3) the search for tools that may predict the patients who may benefit from fluid and those who do not. Meanwhile, clinicians should seek to avoid fluid administration where it is unlikely to be of benefit, i.e., where perfusion is adequate, even if vasopressors are needed, or when perfusion is inadequate but fluid responsiveness is unlikely. Following resuscitation, the use of diuretics or ultrafiltration to minimise fluid overload appears safe and may hasten recovery from critical illness. This is reflected in the dynamic phases (ROSE) of fluid management. Finally, while these represent broadly applicable principles, refinement of physiological measurements or biomarkers may allow a more personalised approach to fluid management in the future. In analogy to the well-known concept of antibiotic stewardship, it is thus time for fluid stewardship in the critically ill, where fluids should also be treated as drugs.

参考文献：略