【在线速递】ICU房颤

Atrial fibrillation (AF) is the most common arrhythmia encountered in the ICU. Preexisting AF is highly prevalent among older patients with chronic conditions who are at risk for critical illness, whereas new-onset AF can be triggered by accelerated atrial remodeling and arrhythmogenic triggers encountered during critical illness. The acute loss of atrial systole and onset of rapid ventricular rates that characterize new-onset AF often lead to decreased cardiac output and hemodynamic compromise. Thus, new-onset AF is both a marker of disease severity as well as a likely contributor to poor outcomes, similar to other manifestations of organ dysfunction during critical illness. Evaluating immediate hemodynamic effects of new-onset AF during critical illness is an important component of rapid clinical assessment aimed at identifying patients in need of urgent direct current cardioversion, treatment of reversible inciting factors, and identification of patients who may benefit from pharmacologic rate or rhythm control. In addition to acute hemodynamic effects, new-onset AF during critical illness is associated with both short- and long-term increases in the risk of stroke, heart failure, and death, with AF recurrence rates of approximately 50% within 1 year following hospital discharge. In the absence of a strong evidence base, there is substantial practice variation in the choice of strategies for management of new-onset AF during critical illness. We describe acute and longterm evaluation and management strategies based on current evidence and propose future avenues of investigation to fill large knowledge gaps in the management of patients with AF during critical illness.

心房颤动(房颤)是ICU最常见的心律失常。老年慢性病患者常合并房颤，其罹患重症疾病的风险高，重症疾病期间加速的心房重构和致心律失常触发因子均可促进新发房颤的发生。新发房颤可导致心房收缩功能丧失和心室率加快，进而导致心输出量下降和血流动力学不稳。因此，新发房颤既是疾病严重程度的标志，也可能与患者预后不良相关，是重症疾病器官功能障碍的临床表现。重症疾病期间新发房颤时快速评估血流动力学可识别需要紧急电复律的患者，消除可纠正的诱因，鉴别可能从控制室率或节律控制中获益的患者人群。此外，重症疾病期间新发房颤与短期和长期的卒中、心力衰竭和死亡的风险增加相关，且患者出院后1年房颤的复发率高达50%。因缺乏强有力的循证医学证据，在临床实践中重症疾病期间新发房颤的治疗策略尚未达成共识。本文基于现有的证据描述了重症疾病期间房颤患者即刻和长期的评估和管理策略，展望了未来的发展方向，旨在填补重症疾病期间房颤患者管理的空白。

Keywords: atrial fibrillation; critical illness; sepsis

关键词：心房颤动；重症疾病；脓毒症

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with a lifetime risk in the community of 25% and associated complications of heart failure, stroke, and death. As a comorbidity of aging, preexisting AF is common among patients presenting to the ICU. As a frequent complication of critical illness, new-onset AF is also a problem familiar to ICU physicians. Thus, clinicians encounter either prevalent (preexisting) or incident (newonset) AF among nearly one in three critically ill patients.

心房颤动是最常见的持续性心律失常，其终生风险为25%，并与心衰、卒中和死亡的风险增加相关。房颤是一种年龄依赖性疾病，ICU患者常合并房颤。作为一种重症疾病常见的合并症，新发房颤也成为ICU医生面临的一道难题。因此，约三分之一的重症患者合并房颤。

The present review discusses the clinical impact of, and evidence-based approaches to, AF in critically ill patients, with specific consideration of risk factors, pathophysiology, treatments, and outcomes of newonset AF during critical illness.

本文讨论了房颤对重症患者的临床影响和基于循证医学证据的房颤治疗策略，重点强调了重症疾病期间新发房颤的危险因素、病理生理、治疗和临床结局。

重症疾病期间的新发房颤：危险因素和发病机制

New-onset AF During Critical Illness: Risk Factors and Mechanisms

Mechanisms of new-onset AF during critical illness are only partially elucidated. To better grasp the mechanisms and risk factors of AF during critical illness, we first review the current understanding of the mechanisms of AF in the community setting.

目前对重症疾病期间新发房颤的发病机制认识有限。为了更好地理解重症疾病期间房颤的发病机制和危险因素，我们首先回顾下房颤的发病机制。

Sustained AF is believed to occur through a two-step process that includes the following: 1) the formation of an arrhythmogenic atrial substrate as fertile ground for the development of AF, and 2) the “seed” that initiates AF through an arrhythmogenic trigger. Remodeling of atria into a proarrhythmic substrate is most often due to the development of atrial fibrosis. Chronic heart failure, hypertension, valve disease, and myocardial infarction result in multiple, common pathways of inflammation, renin-angiotensin system activation, and generation of reactive oxygen species that produce atrial fibrosis. In addition to atrial fibrosis, persistent tachycardia can produce electrical remodeling that leads to an atrial substrate susceptible to AF through changes in intracellular calcium ion handling and ion channel expression. AF may be initially triggered through multiple factors that perturb normal electrical conduction such as hypokalemia, hypomagnesemia, hypovolemia, and alterations in parasympathetic and sympathetic activity, leading atrial foci to develop abnormal automaticity, self-sustaining action potentials, or re-entrant circuits. When arrhythmogenic triggers occur in the absence of an arrhythmogenic substrate, AF is generally fleeting and self-terminating. However, when arrhythmogenic triggers combine with atrial fibrosis or electrical remodeling, AF can be sustained and becomes increasingly difficult to terminate through further electrical remodeling.

房颤持续主要是通过以下两个步骤:1)致心律失常性心房基质的形成是房颤发生的基石，2)诱因触发。心房重构至致心律失常性基质最常见的原因是心房纤维化。慢性心力衰竭、高血压、瓣膜病和心肌梗死可通过多种途径导致炎症、肾素-血管紧张素系统激活和活性氧的产生，进而促进心房纤维化。此外，持续性心动过速还可通过改变细胞内钙处理和离子通道表达导致心房电重构，促进房颤易感性。低钾血症、低镁血症、低血容量以及副交感神经和交感神经功能紊乱等多种诱因可通过扰乱正常的电传导而诱发房颤，导致心房局部的自主节律性增高、动作电位及折返环的形成。若心房内无致心律失常性基质，房颤常为一过性且可自行终止。然而，若心房存在心房纤维化或电重构，房颤常呈持续性发作，且可进一步加重心房电重构导致转窦困难。

Although critical illness-induced AF also likely follows the development of a susceptible atrial substrate combined with a triggering event, the specific factors that contribute to the arrhythmogenic substrate and the specific triggers may differ from community-acquired AF. For example, traditional risk factors associated with AF in the community setting (ie, structural and valvular heart disease) have not been consistently linked to newonset AF during critical illness.14 Rather, emerging evidence suggests that acute events during critical illness accelerate cardiac remodeling and fibrosis to rapidly produce a susceptible atrial substrate, providing fertile ground for the development of sustained AF in response to the myriad arrhythmogenic triggers of critical illness.

尽管重症疾病诱发的房颤也可能加重心房底物的易感性，且常存在触发因素，但导致致心律失常底物发生的因素和具体触发因素可能不同于非重症疾病相关的房颤。如与房颤相关的传统危险因素(即结构性和瓣膜性心脏病)与重症疾病期间新发房颤的相关性并不一致。此外，有证据表明重症疾病期间的急性事件可加速心脏重构和纤维化，迅速产生致心律失常性的心房基质，为重症疾病期间心律失常诱发因子诱导持续性房颤的发生奠定了基础。

重症疾病和心房重构

Critical Illness and Atrial Remodeling

Accelerated cardiac structural and electrical remodeling can occur due to infection and inflammation that are common during critical illness. Murine and primate models of pneumonia show that bacteria deposit within the myocardium and result in development of atrial fibrosis and an arrhythmogenic substrate, despite treatment with antibiotics. Bacteria can also alter calcium ion channel gene expression through toxin release, resulting in a shortened atrial-effective refractory period which produces electrical remodeling that further predisposes to AF during sepsis.

重症疾病期间严重的感染和炎症可加速心脏的结构重构和电重构。小鼠和灵长类动物肺炎模型提示，即使给予抗生素抗感染治疗，细菌仍可沉积在心肌内，导致心房纤维化和致心律失常性基质。细菌释放毒素改变了钙离子通道的基因表达，导致了心房有效不应期缩短，促进了心房的电重构，进而导致脓毒症患者房颤易感性增加。

Inflammation, regardless of the presence of infection, may also play a role in the development of AF. Elevated inflammatory markers in patients with sepsis and postoperative patients are associated with an increased risk of developing AF. Inflammation may predispose to arrhythmia development as a result of direct inflammatory cell infiltration and oxidative damage to atrial myocytes. Inflammation and oxidative damage may also help explain associations between obesity and new-onset AF, both in the community and during critical illness. In turn, early reports suggest that anti-inflammatory agents such as glucocorticoids and statins may decrease the incidence of AF; these agents warrant further study.

感染性和非感染性炎症在房颤的发生中具有重要作用。脓毒症患者及术后患者炎症指标的升高与房颤的发生风险增加相关，其原因可能是心房肌细胞炎症细胞的浸润和氧化损伤。无论是非重症疾病期间的房颤还是重症疾病期间的房颤，炎症和氧化损伤可能有助于解释肥胖和新发房颤的相关性。既往研究表明，抗炎药物如糖皮质激素和他汀类药物可能会降低房颤的发生率，然而疗效尚需进一步研究。

重症患者发生房颤的诱发因素

AF Triggers During Critical Illness

In the ICU, AF is more frequent among patients receiving vasopressor agents, in patients with electrolyte derangements, and in patients with greater disease severity. For example, hypokalemia and changes in the balance of autonomic activity as a result of vasopressors may alter ion channel activity and cell automaticity that predispose to AF. Dopamine and epinephrine in particular have chronotropic effects that can lead to increased atrial ectopic discharges triggering new AF. Greater illness severity is also associated with the risk of new AF development, which may be a consequence of increased release of catecholamines and progressive autonomic dysfunction. Lastly, atrial size on echocardiography is associated with new-onset AF in the ICU, suggesting that iatrogenic atrial pressure/volume overload may also be important in the development of AF in the critically ill. Figure 1 summarizes proposed mechanisms for AF development in patients who are critically ill.

在ICU中，房颤常见于接受血管活性药物治疗、电解质紊乱及病情较严重的患者中。如低钾和血管活性药物导致的自主神经功能紊乱均可改变离子通道活性和细胞的自主节律，增加了房颤的易感性。多巴胺和肾上腺素具有心脏变时作用，可增加心房异位起搏点兴奋性，进而诱发房颤。较严重的疾病也与新发房颤的发生相关，其原因可能是儿茶酚胺释放增加和渐进性自主神经功能障碍。最后，心房大小也与ICU中新发房颤相关，提示在重症疾病中，医源性心房压力/容量负荷对房颤的发生具有重要作用。图1总结了重症患者房颤的发生机制。

Figure 1 – Proposed mechanisms and risk factors for new-onset AF during critical illness. AF develops through a two-step process: creation of an arrhythmogenic substrate followed by a triggering event. During critical illness, both acute (dark blue boxes) and chronic risk factors (light blue boxes) have roles in the development of AF. Prior to critical illness, chronic risk factors for AF may alter the normal atrial myocardium into an arrhythmogenic substrate predisposing to AF during critical illness. During critical illness, patients with both normal and arrhythmogenic atria can develop new-onset AF in the setting of acute risk factors. Risk factors potentially lead to accelerated structural and electrical remodeling and may then trigger AF through multiple mechanisms, including adrenergic stimulation. Proposed pathways by which these risk factors lead to AF may be optimal targets for future preventative strategies. AF = atrial fibrillation; CHF = congestive heart failure; CKD = chronic kidney disease; ROS = reactive oxygen species; TGF = transforming growth factor.

图1. 重症疾病期间新发房颤的机制和危险因素。房颤的发生过程包括致心律失常基质的产生和房颤触发。重症疾病期间，急性(深蓝色方框)和慢性危险因素(浅蓝色方框)在房颤的发生中具有重要作用。重症疾病发生之前，房颤的慢性危险因素改变了正常心房肌促进致心律失常基质的产生，导致重症疾病期间房颤的易感性增加。无论患者的心房是否存在致心律失常性基质，房颤的急性危险因素可促进重症疾病期间新发房颤的发生。危险因素可能会加速心房的结构重构和电重构，然后通过多种机制触发房颤，如肾上腺素的刺激。房颤危险因素介导的房颤发生途径可作为未来预防房颤的靶标。AF = 房颤; CHF = 充血性心力衰竭; CKD = 慢性肾脏疾病; ROS = 活性氧; TGF =转化生长因子.

重症疾病期间预测新发房颤

Prediction of New-onset AF During Critical Illness

Tools that identify patients at high risk for new-onset AF during critical illness may inform mechanisms of AF, identify potential targets for intervention, and enrich future trials studying AF preventative strategies. Klein Klouwenberg et al recently developed a prediction tool for new-onset AF based on clinical factors, including time since admission, age, obesity, immunocompromise, elevation of inflammatory markers, shock, renal failure, potassium level, and FIO₂. This tool can identify the risk for AF in patients with sepsis with a C statistic of 0.81 (https://safescore./safe).

鉴别重症疾病期间新发房颤高危患者的工具有助于揭示房颤的发生机制，识别潜在的治疗靶点，有助于推进未来房颤预防策略的研究。近期，Klein Klouwenberg等人开发了一种基于临床因素(包括入院时间、年龄、肥胖、免疫功能受损、炎症标志物升高、休克、钾和FIO₂) 预测新发房颤的工具。该工具可以预测脓毒症患者房颤的发生风险，C统计量为0.81。

重症患者房颤的临床结局

Clinical Consequences of AF during Critical Illness

AF may lead to clinical decompensation through interrelated mechanisms. During AF, the coordinated depolarization and contraction of the heart is disrupted by innumerable, disorganized atrial electrical impulses leading to erratic contraction and loss of the “atrial kick” that assists with ventricular filling during diastole. Patients with diastolic dysfunction may be prone to hemodynamic decompensation during episodes of AF because of the increased reliance on the “atrial kick” during left ventricular filling. Loss of atrial systole may be particularly important in critical illnesses such as sepsis, during which approximately one half of patients have impaired ventricular relaxation. In critical illness, excess sympathetic tone can also alter the depolarizing properties of conducting fibers in the atrioventricular (AV) node, allowing increased conduction of atrial impulses to the ventricles and rapid ventricular responses (RVRs) that further impair cardiac output. In one study evaluating hemodynamic consequences of new-onset AF during critical illness, 37% of critically ill patients with new-onset AF developed immediate hemodynamic instability, 25% had heart rates > 150 beats/min, and 11% exhibited new signs of cardiac ischemia and heart failure. Thus, although AF during critical illness often presents during times of high disease severity, it also seems to increase the severity of the disease itself.

房颤可能通过相关机制导致临床失代偿。房颤时，快速无序的心房电冲扰乱了心脏正常的去极化和收缩，导致心房收缩功能丧失，降低了舒张期心室充盈。舒张功能不全的患者在房颤发作期间更易出现血流动力学不稳，因为在舒张期心房收缩功能对舒张功能不全患者的心室充盈发挥重要作用。心房收缩功能在重症疾病如脓毒症中至关重要，因约50%的脓毒症患者存在舒张功能不全。在重症疾病中，交感神经张力的增加可改变房室结传导束的去极化特性，增加了房室传导和加快了心室率，进一步降低了心输出量。一项评估重症疾病期间新发房颤血流动力学结局的研究提示37%的重症患者出现新发房颤后，患者立即出现血流动力学不稳，25%的患者心率> 150次/分，11%表现出心肌缺血和心力衰竭的体征。因此，重症疾病期间房颤常预示着疾病的严重性，但房颤本身使疾病进一步恶化。

重症患者发病及好转后发生房颤的预后

Outcomes of AF During and After Critical Illness

Because development of AF during critical illness is associated with more severe illness prior to onset, as well as clinical worsening following onset, ascertaining the causal role of AF in patient outcomes is difficult. In one study of 1,782 patients admitted to the ICU with sepsis, 418 (23%) developed new-onset AF; the new-onset AF was associated with increased hospital mortality after accounting for competing risks and multiple, timevarying cofounding variables (subdistribution hazard ratio, 2.10 [95% CI, 1.61-2.73]). Multiple other studies have identified associations between new-onset AF and increased risk of death during sepsis and critical illness. Thus, new-onset AF is a dysfunctional cardiac response to infection with strong prognostic implications beyond traditional organ dysfunction measures (eg, Sequential Organ Failure Assessment) and may represent an underrecognized sepsis-defining organ dysfunction.

重症疾病期间房颤的发生与发病前较严重的疾病以及发病后临床恶化相关，因此很难确定房颤在预后中的因果作用。在一项入选了1782例因脓毒症入住ICU的研究中，418例(23%)患者出现了新发房颤，在考虑竞争风险和多个具有时变效应的协变量后，新发房颤与院内死亡率增加相关(子分布危险比，2.10 [95% CI, 1.61-2.73])。既往多项研究已明确新发房颤与脓毒症和重症疾病期间患者死亡风险增加的相关性。因此，新发房颤是因感染引起的宿主反应失调导致的心脏功能障碍，其对预后的影响优于传统的器官功能障碍测量方法(如序贯器官衰竭评估)，房颤可能是一种尚未被认识到的定义脓毒症的器官功能障碍。

Among survivors of critical illness, new-onset AF frequently resolves prior to discharge, and thus “secondary AF” has long been thought of as a selflimited event in patients in whom the AF trigger is transient. However, emerging evidence suggests that AF following critical illness often reoccurs after resolution of the critical illness and that long-term outcomes following critical illness may be associated with arrhythmia persistence or reoccurrence. For example, in a large observational study, 55% of patients with newonset AF who survived a sepsis hospitalization had AF occurrence within 5 years compared with 16% of patients who did not have AF during a sepsis hospitalization. Interestingly, patients with new-onset AF during sepsis had higher 5-year risks of ischemic stroke, heart failure, and death compared with patients with no AF but a reduced risk compared with patients with preexisting AF. These data suggest a potential pathway in which new-onset AF during critical illness increases the risk of recurrent AF following critical illness, which then increases the risk of long-term poor outcomes. Thus, AF during sepsis may contribute to the development of the “post-ICU syndrome” and may represent an opportunity for intervention to improve long-term outcomes following critical illness.

重症疾病的幸存者出院前新发房颤常可转复窦律，因此，“继发性房颤”长期以来被认为是一种自限性疾病。然而，目前有证据表明，重症病患者治愈后可出现房颤复发，重症病患者治愈后的长期预后可能与心律失常的持续或复发相关。如在一项大型的观察性研究中，与16%脓毒症住院期间未发生房颤的幸存者相比，55%脓毒症住院期间合并新发房颤的幸存者5年内出现房颤的复发。有趣的是，脓毒症住院期间出现新发房颤患者的5年缺血性卒中、心力衰竭和死亡风险高于无房颤的患者，但与既往有房颤病史的患者相比，其风险降低。上述的数据表明重症疾病期间新发房颤的发生增加了重症患者治愈后房颤复发的风险，使其长期不良预后的风险增加。因此，脓毒症患者新发房颤可能促进了“ICU后综合征”的发生，可能为进一步干预并改善重症疾病幸存者的长期预后提供了机会。

急性房颤的治疗

Acute Management

Breaking the self-propagating cycles of AF and disease progression represents a potential target to improve outcomes during and following critical illness. The treatment priorities of AF in the ICU depend on multiple factors, including the goals of care of the patient, inciting events/reversible triggers, comorbid disease, hemodynamic effects, and the risks of potential therapeutic agents. Within this context, we recommend a multifaceted approach to the management of acute AF in critical illness based on current physiological understanding and observational evidence. Therefore, a general approach to AF in the ICU setting includes the following: (1) assessment for potential hemodynamic effects and mechanisms of hemodynamic change likely attributable to AF, (2) removal of offending agents that increase the risk for AF (ie, beta-agonists) and/or correction of reversible arrhythmogenic triggers (electrolyte imbalances, airway obstruction, and atrial stretch), and (3) choice of an initial treatment strategy that maximizes potential benefit and minimizes risk when AF seems to be causing harm. Considerations for initial pharmacologic strategies include rate control when adverse effects of AF seem due to an elevated heart rate, or rhythm control when adverse effects of AF may be due to loss of atrial systole, or where a rate control strategy is ineffective or has unacceptable side effects. In the event of precipitous hemodynamic compromise duento AF, urgent direct current cardioversion (DCCV) should be used. Finally, patients should be assessed for candidacy for arterial thromboembolism prophylaxis. Figure 2 summarizes treatment priorities of new-onset AF during critical illness (outlined in the following sections).

打破房颤的折返激动和疾病进展可改善重症疾病期间及治愈后患者的预后。ICU房颤的治疗优先级取决于多种因素，包括患者的治疗目标、触发因素/可纠正的诱因、合并症、血流动力学、治疗风险等。基于目前对重症房颤生理学的理解和证据，我们推荐从不同方面来管理重症患者的急性房颤。因此，ICU房颤的一般处理原则包括：（1）评估房颤对血流动力学的影响及其机制；（2）消除房颤的致病因子(如β受体激动剂)和/或纠正可逆性心律失常的诱发因素(电解质失衡、气道阻塞和心房牵张)；（3）若房颤可引起不良事件，权衡利弊后，初始治疗策略的选择应使患者的获益最大化，风险最低化。初始药物治疗策略包括控制室率和转复窦律，对于快室率的房颤应该考虑药物控制心室率；若房颤导致心房收缩功能丧失而影响患者的心功能时或者室率控制效果欠佳或出现药物不良反应时应考虑转复窦律。若房颤导致血流动力学不稳定，应采用紧急的直流电复律。最后，应评估患者的血栓栓塞风险，必要时给予抗凝药物预防血栓栓塞。图2总结了重症疾病期间新发房颤的治疗策略 (概述如下)。

Figure 2 – Acute management priorities in new-onset AF during critical illness. Identification of new-onset AF during critical illness should prompt a four-step rapid clinical assessment: (1) assessment for hemodynamic compromise requiring urgent DCCV, (2) removal of potential offending agents, (3) reversal of inciting acute factors, and (4) treatment to reduce rate or convert to sinus if AF persists and is associated with adverse effects. DCCV = direct current cardioversion; HR = heart rate. See Figure 1 legend for expansion of other abbreviation.

图2. 重症疾病期间新发房颤治疗策略的优先级。重症疾病期间新发房颤临床快速四步评估法：（1）评估血流动力学，决定是否给予紧急的直流电复律；（2）消除房颤致病因子；（3）去除房颤急性诱因；（4）若房颤持续存在且伴有不良反应，可选择控制心室率或转复窦律。DCCV ：直流电复律，HR 心率。CCB：钙离子通道阻滞剂，其他缩写同图1。

直流电复律

Direct Current Cardioversion

In hemodynamically unstable patients with AF with RVR or when AF with RVR contributes to ongoing myocardial ischemia, the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society 2014 guidelines make a strong recommendation, based on limited evidence, for DCCV. Despite this recommendation, the success rates of attempted cardioversion of AF during critical illness are low: in postoperative patients who developed AF, attempted cardioversion resulted in immediate conversion to sinus rhythm (SR) in 71% of patients, but after 1 h, only 43% patients remained in SR, and after 24 h, only 23% patients remained in SR. Thus, in critically ill patients in whom cardioversion is attempted, concurrent administration of rate or rhythm control therapy should be considered given the high likelihood of AF recurrence soon after a successful cardioversion attempt. When DCCV is used during critical illness, there is often inadequate time or patient stability to assess for left atrial thrombus. In addition, comorbid disease (ie, coagulation defects, recent stroke) is often present, which increases the risk of instituting anticoagulation. It is unknown if administering anticoagulation in critically ill patients prior to DCCV decreases the risk of thromboembolic events or if there is an optimal timing of anticoagulation prior to DCCV. Thus, we recommend that the decision to administer periprocedural anticoagulation be informed by the urgency of DCCV and relative or absolute contraindication to such therapy.

对于血流动力学不稳定的快室率房颤患者或快室率房颤导致持续心肌缺血的患者，2014年AHA/ACC/HRS指南基于现有的证据强烈推荐直流电复律。然而，重症疾病期间房颤患者直流电复律的成功率低：术后房颤患者电复律即刻电转复成功率为71%，但1小时后，仅43%患者仍维持窦性心律，24小时后，仅23%的患者保持窦性心律。因此，考虑到电转复成功后房颤复发风险较高，重症患者通过电复律转复时，可同时给予药物控制心室率或节律控制。重症患者行电复律时，通常因时间不足或者病情不稳定而无法当评估左心房血栓。此外，患者常合并凝血功能障碍、近期卒中等疾病，增加了抗凝治疗的风险。目前对于在电复律前给予重症患者抗凝治疗能否降低血栓栓塞的风险或电复律前是否存在最佳的抗凝时机尚未明确。因此，我们建议在决定是否行围手术期抗凝治疗时，应考虑电复律的紧迫性及其是否存在抗凝治疗的相对或绝对禁忌症。

室率控制或转复窦律的药物选择

Medication Options for Rate and Rhythm Control

In critically ill patients without severe hemodynamic decompensation resulting from AF, clinicians have a range of medical therapies to consider for rate or rhythm control. Frequently chosen rate control medications are nondihydropyridine calcium channel blockers (CCBs), beta-blockers (BBs), and cardiac glycosides such as digoxin. Medications selected for rhythm control most often include magnesium and amiodarone, both of which have rhythm- and rate-controlling properties. CCBs, such as verapamil and diltiazem, inhibit voltagegated calcium channels, decreasing depolarization of the AV node and slowing heart rate; however, these agents also have vasodilatory and negative inotropic effects and are contraindicated in patients with acute heart failure. BBs have rate-controlling, negative inotropic and vasodilatory effects similar to CCBs, but they function as sympatholytic agents through antagonism of the beta1-receptor, leading to decreased conduction through the AV node and reduced effects of catecholamines on the myocardium. A distinct pharmacokinetic advantage of BBs is the ultra-short-acting preparation esmolol, which allows rapid titration and discontinuation with fast recovery from potential drug-related hypotension. Digoxin slows heart rate by increasing vagal tone; it is associated with low rates of hypotension but has a narrow therapeutic index. Observational studies show associations between digoxin use and increased mortality, especially in patients with underlying heart failure with serum digoxin levels > 1.2 ng/ml. In addition, the vagomimetic effects of digoxin may be less effective during critical illnesses characterized by high catecholamine states. Magnesium affects ion channel activity to decrease cardiac automaticity and prolong AV node refractoriness, which may improve rate control and lead to SR conversion without substantial negative inotropic activity. Amiodarone inhibits adrenergic stimulation and blocks the delayed rectifier current, which can lead to conversion to SR as well as prolonged AV node refractoriness slowing AV conduction. A main advantage of amiodarone, unlike several other antiarrhythmic agents, is that it is not contraindicated in patients with structural or coronary heart disease. Potential disadvantages to amiodarone are hypotension during IV infusion and pro-arrhythmic and organ toxicity effects, including an increased risk of chronic interstitial pneumonitis and organizing pneumonia. Acutely, amiodarone lung toxicity can mimic ARDS.

无血流动力学紊乱的重症房颤患者，临床医生可通过不同的药物控制室率或转复。常用的室率控制药物包括非二氢吡啶钙通道阻滞剂(CCBs)，β受体阻滞剂(BBs)和强心苷类药物，如地高辛。用于转复窦律的药物通包括镁剂和胺碘酮，这两种药物都具有控制室率和转复窦律的特性。CCBs，如维拉帕米和地尔硫卓，可抑制电压门控钙通道，减少房室结的去极化和降低心率；然而，这些药物也具有血管扩张和负性肌力作用，禁用于急性心力衰竭患者。BBs与CCBs类似，具有控制心室率、负性肌力和血管扩张作用，但其主要通过拮抗β1受体拮抗交感神经，减慢房室结的传导，降低儿茶酚胺对心肌的作用。BBs显著的药代动力学优势是其超短效制剂艾司洛尔，起效迅速，停药后可快速纠正药物相关的低血压。地高辛通过增加迷走神经张力降低心率，其低血压的发生率低，但治疗窗窄。观察性研究表明地高辛与患者的死亡率增加相关，特别是对于合并心力衰竭且血清地高辛水平> 1.2 ng/ml的患者。此外，地高辛的拟迷走效应在重症疾病期间中可能无效，因重症疾病期间患者血清中高儿茶酚胺浓度较高。镁影响离子通道活性以降低心脏自主节律、延长房室结的不应期，进而降低心率及转复窦律，且无明显的负性肌力作用。胺碘酮抑制肾上腺素受体，阻断延迟整流电流，从而转复窦律，并延长房室结的不应期，减慢房室传导。与其他抗心律失常药物不同，胺碘酮的主要优点是可用于结构性心脏病或冠心病患者。胺碘酮的缺点是静脉输注过程时可导致低血压，且胺碘酮具有促心律失常和器官毒性作用，包括增加慢性间质性肺炎和机化性肺炎的风险。尤其是胺碘酮肺毒性类似于急性呼吸窘迫综合征。

There is significant practice variability regarding initial medication choice for AF during critical illness. In the United States, CCBs are administered as initial treatment most frequently (36%) for patients with AF and sepsis, followed by BBs (28%), digoxin (20%). and amiodarone (16%). Practices also vary according to country: a survey of intensivists in the United Kingdom found that > 80% would choose amiodarone as first-line treatment, whereas 12% chose BBs. Despite being a less commonly used initial treatment, preliminary BB use for AF was associated with a lower risk of in-hospital mortality compared with CCBs, digoxin, or amiodarone in an observational analysis among patients with sepsis. In addition, a study using granular ICU data showed that initial use of metoprolol for AF with RVR was associated with lower need for administration of a second agent compared with amiodarone and better rate control at 4 h compared with diltiazem. Other studies suggest that use of esmolol during sepsis enhances arterial elastance and ventricular-arterial coupling, which may improve cardiovascular efficiency and reduce mortality. Thus, use of BBs to treat arrhythmias during critical illness is a promising area of investigation.

重症疾病期间，房颤的初始药物策略并非固定不变。在美国，对脓毒症合并房颤患者常使用CCB作为初始治疗(36%)，其次是BBs(28%)、地高辛(20%)和胺碘酮(16%)。不同国家的初始治疗方案也不同:调查发现在英国的重症病学专家中，80%的医师会选择胺碘酮作为一线治疗，仅12%选择BBs。尽管BB不是常用的初始治疗方案，但与CCB、地高辛或胺碘酮相比，将BB作为脓毒症患者的初始治疗与住院死亡率风险降低相关。此外，ICU的细粒度数据提示，与胺碘酮相比，初次使用美托洛尔治疗快室率房颤疗效好，降低了患者对第二种室率控制药物的需要；与地尔硫卓相比，4小时内的室率控制疗效更佳。其他研究表明脓毒症患者使用艾司洛尔可增强动脉弹性和心室-动脉偶联，进而提高心血管的效率并降低死亡率。因此，使用BBs治疗重症疾病期间的心律失常是非常值得研究的领域。

Two small randomized trials comparing rate vs rhythm control medications in AF with RVR in the acute (but non-ICU) setting supplement observational studies during critical illness. In a single-center study of 150 patients with uncomplicated acute symptomatic AF with RVR requiring hospital admission, randomization to diltiazem was associated with a higher percentage of sustained ventricular rate control (90%) compared with digoxin (74%) and amiodarone (74%) (BBs were not evaluated). In a single-center study of 60 ICU patients with supraventricular tachycardia (AF: n = 57; atrial flutter: n = 2; atrial tachycardia: n = 1), randomization to diltiazem compared with two dosing strategies of amiodarone did not seem to result in different rates of adequate heart rate control within 4 h (70% for diltiazem vs 55% for amiodarone load vs 75% for amiodarone load and maintenance); however, diltiazem was associated with an increased rate of drug discontinuation due to hypotension (30% vs 0% vs 5%, respectively). Given the observational findings of decreased mortality, improved heart rate control, better ventriculo-arterial coupling, and pharmacokinetic advantages, it is reasonable to use esmolol as a first-line treatment for hemodynamically significant AF during critical illness if no contraindications exist. If additional control is needed, second-line agents may include magnesium, diltiazem, and amiodarone, with digoxin reserved for situations in which other agents are ineffective or contraindicated. The strong safety profile of magnesium and similar rate of conversion to SR compared with amiodarone make magnesium a reasonable choice prior to amiodarone if rhythm control strategy is chosen. Table 1 summarizes AF treatment strategies.

作为重症患者观察性研究的补充，两项小的随机试验比较了急性发病(但非ICU)时快室率房颤药物的室率控制和节律控制。一项单中心研究共纳入150例无并发症的急性症状性快室率的房颤且需要住院治疗的患者，与地高辛(74%)和胺碘酮(74%)相比，地尔硫卓可提高持续的室率控制率(90%)(未评估BBs)。一项纳入60例ICU的室上性心动过速患者(房产57例；心房扑动2例；房性心动过速1例)患者的随机试验提示，与两种剂量的胺碘酮相比，地尔硫卓并没有降低4小时内的室率控制率(地尔硫卓：70%，胺碘酮负荷量：55%，胺碘酮负荷量和维持量：75%)；然而，地尔硫卓与因低血压引起的停药率增加有关(分别为30% vs 0% vs 5%)。鉴于观察性研究发现艾司洛尔有助于降低死亡率，改善室率控制，更好的心室-动脉耦合和药代动力学优势，若无禁忌症，将艾司洛尔作为重症疾病期间血流动力学不稳房颤患者的一线治疗是合理的。如果需要联合用药，二线药物治疗包括镁、地尔硫卓和胺碘酮，地高辛可用于其他药物无效或禁忌的情况。如果选择节律控制，镁的安全性高，且维持窦性心律的疗效与胺碘酮类似。因此，可优先选择镁作为节律控制的治疗方案。图1总结了房颤的治疗策略。

亚急性治疗

Subacute Management

After rate and rhythm management of AF during critical illness, the next clinical dilemma is often the decision to start arterial thromboembolism prophylaxis with anticoagulation. Patients with critical illness and AF have a twofold increased risk of in-hospital ischemic stroke compared with those without AF, but they also have higher bleeding risk and often require invasive procedures that may necessitate interruption of anticoagulation; decisions regarding anticoagulation of critically ill patients are complex. In a nationwide study of patients with AF and sepsis in the United States, 35.3% received parenteral anticoagulant agents. In propensity score-matched patients, there was no difference in rate of in-hospital ischemic stroke between patients who received or did not receive parental anticoagulant agents; however, there was an increase in clinically significant bleeding (8.6% vs 7.2%) in the patients who received parenteral anticoagulation. It is unknown if similar associations exist for nonsepsis causes of critical illness. There are currently no anticoagulation guidelines for AF during sepsis; further studies are direly needed to clarify potential benefits/harms prior to standardized treatment being recommended. Given the lack of clear benefit and the potential for harm, in critically ill patients with newonset AF during sepsis who do not have planned cardioversion, we do not currently recommend routinely initiating parenteral anticoagulation for arterial thromboembolism prophylaxis during the acute phases of critical illness.

重症疾病期间房颤的室率和节律控制后，下一个临床难题是开启抗凝治疗预防动脉血栓栓塞。重症疾病期间房颤患者院内缺血性卒中的风险是无房颤患者的两倍，但其出血风险也较高，患者通常需要中断抗凝治疗以进行侵入性手术。因此，重症患者的抗凝治疗决策是复杂的。美国一项针对房颤和脓毒症患者的全国性研究提示35.3%的患者接受了非口服抗凝药物治疗。倾向评分匹配后，接受或不接受非口服抗凝治疗的患者院内缺血性卒中的发生率并无差异；然而，接受非口服抗凝治疗患者的临床出血事件显著增加(8.6% vs 7.2%)。目前尚未明确重症疾病的非脓毒症病因是否存在类似的相关性。目前尚无针对脓毒症期间房颤的抗凝治疗指南，在推荐标准化治疗之前，迫切需要进一步的研究来阐明抗凝治疗的利与弊。因目前尚无证据证实抗凝治疗的利与弊，对于脓毒症期间合并新发房颤的患者若无转复的计划，我们并不推荐在疾病的急性期常规启动非口服抗凝治疗预防动脉血栓栓塞。

长期的管理策略

Approaches to Long-term Management

Following critical illness, decisions to initiate anticoagulation to reduce thromboembolic risk depend on the persistence of arrhythmia, thromboembolic and bleeding risks, and goals of care. AF during critical illness frequently resolves prior to discharge (86% resolution in a single-center study of patients with septic shock), but long-term thromboembolic risk of patients with new AF during critical illness seems to remain relatively high.35 Among survivors who developed new-onset AF during sepsis and who experience an ischemic stroke following the sepsis hospitalization, one half did not have another AF diagnosis recorded prior to the stroke.37 Thus, among patients with new-onset AF during the critical illness that seems to be “resolved,” there may be opportunity to reduce post-critical illness stroke events through increased AF surveillance following hospital discharge.

重症患者好转后，是否启动抗凝治疗预防血栓栓塞取决于患者心律失常的持续时间、血栓栓塞风险和出血风险及治疗目标。重症病期间房颤通常在出院前可转复窦律(一项脓毒性休克的单中心研究中，房颤的转复成功率为86%)，但重症疾病期间新发房颤患者的长期血栓栓塞风险仍然较高。脓毒症期间患者出现新发房颤，且出院后出现缺血性卒中的患者，约50%的患者在卒中前无房颤的诊断记录。因此，重症疾病期间新发房颤转复窦律后，看似房颤已治愈，但患者出院后仍需密切监测来降低重症疾病后的卒中事件。

In patients without contraindications to anticoagula-tion whose AF persists following hospital discharge, thromboembolism prophylaxis should be initiated in those not at low risk (as determined by using CHA₂DS₂VASc [congestive heart failure, hyperten-sion, age ≥ 75 years, diabetes, previous stroke/ transient ischemic attack, vascular disease, age 65 to 74 years, sex category] score). Once the decision is made to initiate anticoagulation, we agree with the 2014 guideline recommendations of the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society regarding choice of anticoagulant medication. The timing of prophylaxis initiation should be informed according to the patient’s goals of care, renal function, bleeding risk, and medication interactions. For patients who have no evidence of AF persistence following critical illness, measures should be instituted to facilitate detection of subclinical AF. Specifically, outpatient cardiac monitoring should be considered in patients without AF persistence but with elevated CHA₂DS₂VASc scores to identify patients who may benefit from anticoagulation, a strategy that has shown promise in patients following cryptogenic stroke.

无抗凝禁忌症的房颤患者出院后，应根据血栓栓塞风险评分明确是否需要开启抗凝治疗预防血栓栓塞。CHA₂DS₂-VASc评分(充血性心力衰竭、高血压、年龄在75岁及以上、糖尿病、既往卒中/短暂性脑缺血发作、血管疾病,年龄在65-74岁，性别)为1分（女性）或0分（男性）为血栓低风险人群，建议在非低风险人群中启动抗凝治疗。一旦开启抗凝治疗，应根据2014年AHA/ACC/HRS指南选择合适的抗凝药物。抗凝治疗的启动时机主要取决于患者的治疗目标、肾功能、出血风险和药物相互作用。重症患者治愈后若房颤已转窦，应严密监测是否存在亚临床房颤。注意，对于无房颤发作但CHA₂DS₂-VASc评分升高的患者，应在门诊行心脏监测以识别可从抗凝治疗中获益的患者人群，其临床价值已在隐源性卒中患者中有所体现。

AF = atrial fibrillation; AV = atrioventricular; HR = heart rate; RVR = rapid ventricular rate; SR = sinus rhythm; SVT = supraventricular tachycardia.

^aStudies of treatment efficacy of AF during critical illness are limited. Thus, inclusion of arrhythmia type (AF, atrial flutter, and SVT) and context (critical illness, noncritical illness, or postoperative) are included.

RVR：快心室率；SVT：室上速

a：重症疾病期间房颤治疗疗效的研究有限。因此，研究包括了不同的心律失常类型(房颤、心房扑动和SVT)和临床背景(重症疾病、非重症疾病或术后)。

房颤预防 

Prevention of AF

Prevention of new-onset AF in the ICU is an appealing strategy to potentially improve outcomes and mitigate the often-difficult short- and long-term management of critically ill patients who have AF with RVR. To date, few studies have analyzed prevention of AF in the general ICU setting. In a recent, prospective nonrandomized study, the administration of hydrocortisone in patients with septic shock was associated with lower rates of new-onset AF following propensity score matching. Randomized trials have shown lower rates of new-onset AF following cardiac surgery in patients administered magnesium infusions, glucocorticoids, and BBs; it is unknown whether these strategies are of benefit in a general ICU population. Specific therapies to reduce AF during critical illness cannot be recommended at this time.

ICU中预防新发房颤可改善合并快室率房颤重症患者的预后，降低其短期和长期管理的难度。迄今为止，很少有研究分析ICU患者房颤的预防。近期，一项前瞻性非随机研究提示，倾向评分匹配后，脓毒性休克患者使用氢化可的松与新发房颤的发生率低相关。随机试验表明，在给予镁、糖皮质激素和BBs的患者中，心脏手术后新发房颤的发生率较低；尚未明确这些治疗策略能否使ICU患者获益。目前尚不推荐采用特异性的治疗策略降低重症患者房颤的发生。

展    望

Future Considerations

Future studies of AF in the ICU will help guide our ability to predict, prevent, and manage this frequent and potentially devastating arrhythmia. Improvements in technology to identify the timing and duration of AF in the ICU using automated detection algorithms and mining of large ICU electronic medical records will help us to understand the temporal association between risk factors and AF and potentially inform mechanisms (projectreporter.nih.gov [1R01HL136660-01]). Longterm AF detection techniques may also help to identify patients following ICU hospitalizations who are most likely to benefit from thromboembolism prophylaxis. Randomized trials to address gaps in our knowledge of acute rate and rhythm control therapies in the critically ill are ongoing, assessing the effect of magnesium infusions on AF with RVR in the ICU75 and specific dosing strategies of amiodarone for AF during sepsis.76 Further randomized trials are needed to identify the optimal rate or rhythm strategy for patients in the ICU and to clarify the differences, if present, between specific medications within these strategies.

进一步开展对ICU房颤的研究将有助于指导我们预测、预防和管理房颤。目前采用自动检测算法和挖掘大量ICU电子病历来预测ICU房颤的发病时机和持续时间，有助于帮助我们理解危险因素和房颤之间的时间关联及其发病机制(projectreporter.nih.gov [1R01HL136660-01])。长期房颤检测技术有助于鉴别ICU住院患者中最有可能从预防血栓栓塞中获益的人群。目前正在进行的随机试验有助于填补我们对重症患者急性心率和节律控制治疗的知识盲区，评估ICU中镁剂对快室率房颤的影响，以及脓毒症期间胺碘酮治疗房颤的具体剂量。未来尚需要随机试验来明确ICU房颤患者最佳的室率或节律控制策略及不同治疗方案中不同药物之间的疗效差异(如果不同药物之间存在疗效差异)。

END

翻    译

吴转转  医学博士

山东第一医科大学附属省立医院住院医师

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翻译：吴转转

编辑：宋   璇

审校：王春亭