血液透析抗凝方法
Methods of Hemodialysis Anticoagulation  下载PDF

標準肝素抗凝治療
Standard Heparin Anticoagulation

未分馏肝素（UFH）是血液透析期間最常用的抗凝劑。UFH 與抗凝酶 III 結合，誘導構象變化，導致這種天然抗凝劑的活性增加。這導致凝血因子如 Xa 因子和凝血酶的失活加速（圖 10.1）。UFH 價格實惠、可靠、易於逆轉，並且在確定患者的肝素劑量後需要的醫護人員干預最少。UFH 在懷孕期間也可以安全使用，因為它不會穿過胎盤。儘管肝素相對耐受性良好，但其使用仍存在某些已知的風險和併發症，包括出血風險增加、肝素誘導的血小板減少症（HIT）、高三酸甘油脂血症、過敏反應、瘙癢、骨質疏鬆，並且罕見的高鉀血症。
Unfractionated heparin (UFH) is the most commonly used anticoagulation agent during hemodialysis. UFH binds to the enzyme antithrombin III, inducing a conformational change that leads to an increased activity of this natural anticoagulant. This results in accelerated inactivation of coagulation factors, such as factor Xa and thrombin ( Fig. 10.1 ). UFH is affordable, reliable, easily reversible, and requires minimal staff intervention after a patient's heparin dose is determined. UFH can also be safely used during pregnancy since it does not cross the placenta. Although heparin is relatively well tolerated, there are certain known risks and complications associated with its use, including increased risk of bleeding, heparin- induced thrombocytopenia (HIT), hypertriglyceridemia, hypersensitivity reactions, pruritus, osteoporosis, and rarely hyperkalemia.

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凝血級聯的示意圖及不同抗凝劑的靶點。
Schematic Representation of the Coagulation Cascade and Targets of Different Anticoagulants.

未分馏肝素（UFH）與抗凝血酶結合，間接抑制 Xa 因子和凝血酶。低分子量肝素（LMWHs）和肝素類藥物僅抑制 Xa 因子。直接凝血酶抑制劑，如阿格曲班和重組肝素，直接結合並阻止凝血酶，這是將可溶性纖維蛋白原轉化為不可溶性纖維蛋白的關鍵酶。檸檬酸鹽螯合鈣（Ca ^{2 +} ，圓圈），這是凝血級聯反應中許多反應的關鍵輔因子。
Unfractionated heparin (UFH) binds to antithrombin and indirectly inhibits both factor Xa and thrombin. Low-molecular-weight heparins (LMWHs) and heparinoids inhibit only factor Xa. Direct thrombin inhibitors, such as argatroban and recombinant hirudin, directly bind and block thrombin, the key enzyme that converts soluble fibrinogen into insoluble fibrin. Citrate chelates calcium ( Ca ^{2 +} , circles), a key cofactor of many reactions in the coagulation cascade.

UFH 具有快速的作用起始和相對較短的半衰期（在透析患者中約為 1 小時）。然而，重要的是要記住，在血液透析過程中，肝素代謝存在患者之間的變異性。肝素的活性高度取決於患者的體重和其他變數，例如透析器的吸收、紅血球生成素劑量、體外循環的血栓形成性、血流量以及血液透析治療的長度等。
UFH has a rapid onset of action and relatively short half-life (approximately 1 hour in dialysis patients). However, it is important to keep in mind, however, that there is interpatient variability in heparin metabolism during hemodialysis. Heparin activity is highly determined by patient weight and other variables, such as dialyzer absorption, erythropoietin dose, thrombogenicity of the extracorporeal circuit, blood flow, and length of the hemodialysis treatment among others.

在透析期間使用未分馏肝素（UFH）進行抗凝治療可以通過測定活化部分凝血酶時間（aPTT）來監測，目標為基線值的 1.5 至 2 倍。然而，這種方法需要頻繁測試，導致成本增加和重複抽血。另一種選擇是測定活化凝血時間（ACT），可以通過即時檢測設備獲得。ACT 的目標通常是基線值的 80%更高。然而，由於需要嚴格標準化，ACT 的使用不頻繁，這導致了質量保證和監管問題。一般來說，大多數門診透析單位不會常規測量抗凝參數，除非有臨床證據顯示透析器凝血（即，目視可見的血塊、體外循環壓力增加等）或過度抗凝的跡象，例如在拔管後針刺部位出現延長出血。除非在少數情況下，我們不會在我們機構的住院和門診設施中定期監測抗凝水平。
Anticoagulation with UFH during hemodialysis can be monitored by the determination of activated partial thromboplastin time (aPTT), which is targeted to 1.5–2 times above baseline value. However, this method requires frequent testing leading to increased cost and repeated blood draws. Another option is the determination of activated clotting times (ACTs), which can be obtained with point-of-care devices. ACT is typically targeted to 80% higher than baseline value. However, ACTs are used infrequently because of the need to be rigorously standardized, resulting in quality assurance and regulatory issues. In general, most outpatient dialysis units do not routinely measure anticoagulation parameters unless there is clinical evidence suggesting of dialyzer clotting (i.e., visual clots, increased extracorporeal circuit pressures, etc.) or signs of over-anticoagulation, such as prolonged bleeding at needle puncture sites following decannulation. Except on rare occasions, we do not regularly monitor anticoagulation levels in the inpatient and outpatient facilities of our institutions.

目前，在美國對於血液透析期間的抗凝劑肝素劑量尚無標準化的規範。存在多種基於經驗的方案，以解決凝血與透析後靜脈穿刺部位出血之間的競爭性問題。這些方法需要最少的工作人員介入，並在大多數門診血液透析單位中是標準做法；然而，對於有顯著出血風險的患者則不適用。通常，在血液透析期間施用肝素需要初始的加載劑量，隨後是可以作為重複的單獨劑量或持續輸注的維持劑量。這些策略確保在整個透析治療過程中進行全身抗凝。常規的重複劑量方案包括將初始劑量的未分馏肝素（通常約為 40–50 IU/kg 體重，或 2000–4000 IU）施用到靜脈通路針中，隨後施用 1000–2000 IU 的中期治療劑量以維持適當的抗凝效果。 另外，肝素建模可以通過初始的推注劑量，隨後持續固定輸注肝素（通常為每公斤體重 10–15 IU/h，或 500–2000 IU/h）來維持 200 到 250 秒的 ACT（正常約為 90 到 140 秒）。肝素輸注應在治療結束前 30–60 分鐘終止，以減少透析後靜脈穿刺出血。一些其他的方案包括使用單一的初始推注劑量而不進行維持劑量，以及在治療過程中以減少的輸注速率給予高推注肝素劑量（即大於 5000 IU），以最小化透析後出血。此外，在實施透析器重用的設施中，將藥效動力學方法納入肝素建模也已被證明能提高透析器重用率。
Currently, there are no standardized heparin dosages for anticoagulation during hemodialysis in the United States. A number of empirically-based protocols exist to address the competing issues of clotting and postdialysis bleeding from venipuncture sites. These methods require minimal staff intervention and are standard in most outpatient hemodialysis units; they are, however, unsuitable for patients with significant bleeding risks. Typically, the administration of heparin during hemodialysis requires an initial loading bolus, followed by a maintenance dose that can be given either as repeated separate boluses or as a continuous infusion. These strategies ensure systemic anticoagulation throughout the dialysis treatment. A routine repeated bolus regimen consists of an initial bolus of UFH (usually about 40–50 IU/kg body weight, or 2000–4000 IU) administered into the venous access needle, followed by a midtreatment dose of 1000–2000 IU to maintain suitable anticoagulation. Alternatively, heparin modeling can be performed using an initial bolus followed by a constant fixed infusion of heparin (usually 10–15 IU/kg body weight/h, or 500–2000 IU/h) to maintain an ACT of 200 to 250 seconds (normal ≈ 90 to 140 seconds). Heparin infusion should be terminated 30–60 minutes prior to the end of treatment to reduce postdialysis venipuncture bleeding. Some other protocols include the use of a single initial bolus dose with no maintenance doses, and the administration of a high bolus heparin dose (i.e., greater than 5000 IU) with decreasing infusion rates, as the treatment proceeds to minimize postdialysis bleeding. Furthermore, in facilities that practice dialyzer reuse, incorporation of a pharmacodynamic approach to heparin modeling has also been shown to increase dialyzer reuse rate.

使用未分馏肝素（UFH）與透析治療相結合，確保在整個透析過程中進行全身抗凝。這種方法可靠，並且在確定患者的肝素劑量後，對醫護人員的干預要求最小。我們機構中使用的三種最常見的標準抗凝方案以及不同的 UFH 方案分別總結在表 10.2 和 10.3 中。
The use of UFH with dialysis therapy ensures systemic anticoagulation throughout the dialysis treatment. It is reliable and requires minimal staff intervention after a patient's heparin dose has been determined. The three most commonly used standard anticoagulation regimens using UFH and different UFH protocols used in our institution are summarized in Tables 10.2 and 10.3 , respectively.

低劑量肝素   Low-Dose Heparin

使用最小劑量肝素是一種替代抗凝策略，適用於因頻繁凝塊而無法完成無肝素血液透析的高出血風險患者。目前，該方案尚無標準劑量。最初，體外循環用 2000 至 5000 IU 的未分馏肝素（UFH）沖洗，然後用生理鹽水沖洗以去除未結合的抗凝劑。一般來說，患者每 30 分鐘接受 500 IU 的肝素推注，以保持活化凝血時間（ACT）不高於基線的 40%（> 150 但< 200 秒）。另外，也可以使用肝素的持續輸注並進行頻繁的 ACT 監測，以達到相同程度的抗凝效果。與使用肝素和原蛋白中和的區域抗凝相比，低劑量肝素方案已被證明能減少高風險患者的出血併發症。這種技術的主要優點是其簡單性。主要缺點是仍然會發生某種程度的全身抗凝，需進行仔細監測。此外，由於涉及使用肝素，這種抗凝方法不適合肝素誘導的血小板減少症患者。
The use of minimum-dose heparin is an alternative anticoagulation strategy for patients with high bleeding risk who are unable to complete heparin-free hemodialysis due to frequent clotting. Currently, there are no standardized dosages for this protocol. Initially, the extracorporeal circuit is rinsed with 2000 to 5000 IU of UFH followed by a saline rinse to remove the unbound anticoagulant. Generally, patients receive boluses of 500 IU of heparin every 30 minutes to keep the ACT no higher than 40% above the baseline (> 150 but < 200 seconds). Alternately, a continuous infusion of heparin with frequent ACT monitoring can be used to achieve the same degree of anticoagulation. Low-dose heparin protocols have been shown to reduce bleeding complications in high-risk patients when compared to regional anticoagulation with heparin and protamine neutralization. The major advantage of this technique is its simplicity. The main disadvantage is that some degree of systemic anticoagulation still occurs, necessitating careful monitoring. Also, because it involves the use of heparin, this method of anticoagulation is not suitable for patients with hehparin-induced thrombocytopenia.

低分子量肝素
Low-Molecular-Weight Heparins

低分子量肝素（LMWHs）是由商業性未分馏肝素（UFH）經化學或酶解聚合物降解而來，其分子量約為 UFH 的三分之一（4000 至 5000 道爾頓，與 UFH 的平均 15000 道爾頓相比）。與 UFH 類似，LMWHs 能夠使 Xa 因子失活（見圖 10.1）。由於 LMWH 分子不含有足夠的糖單位來形成同時結合凝血酶和抗凝血酶所需的三元複合物，因此其抑制凝血酶活性的能力顯著較低。另一個重要的區別是，LMWHs 的抗凝效果不會被魚精蛋白硫酸鹽可靠地逆轉。抗凝監測也與 UFH 不同，因為 LMWHs 的活化部分凝血酶時間（aPTT）並不準確；必須測量肝素類或抗 Xa 因子活性來評估其抗凝活性。目前的建議是在體外循環的靜脈端目標抗 Xa 活性為 0.4–0.6 IU/mL，而在透析治療結束時則應低於 0.2 IU/mL。然而，常規監測通常不需要，僅建議在那些出血風險增加的患者中進行。
Low-molecular-weight heparins (LMWHs) are derived from chemical or enzymatic depolymerization of commercial UFH and are about one-third of the molecular weight of UFH (4000 to 5000 daltons vs. mean 15,000 daltons for UFH). Like UFH, LMWHs inactivate factor Xa (see Fig. 10.1 ). Because LMWH molecules do not contain enough saccharide units to form the ternary complex required to simultaneously bind thrombin and antithrombin, their ability to inhibit thrombin activity is significantly less. Another important difference is that the anticoagulation effect of LMWHs is not reliably reversed by protamine sulfate. Anticoagulation monitoring also differs from UFH in that the aPTT is not accurate with LMWHs; heparinoid or anti–factor Xa activity must be measured to assess their anticoagulant activity. Currently, the recommendations are to aim for an anti-Xa activity of 0.4–0.6 IU/mL in the venous port of the extracorporeal circuit and < 0.2 IU/mL at the end of hemodialysis therapy. However, routine monitoring is typically not required and is recommended only in those patients at increased risk of bleeding.

低分子量肝素（LMWHs）被提議造成的出血和血小板減少比肝素少。低分子量肝素達爾肝素在歐洲國家廣泛使用；然而，在美國，低分子量肝素在血液透析抗凝中的使用非常有限。雖然低分子量肝素已被證明在安全性和療效上與未分級肝素（UFH）相似，但在透析相關出血方面，通常未被發現優於肝素，且其增加的成本可能無法證明其相對於未分級肝素的優先使用是合理的。還需要注意的是，儘管血小板減少症（HIT）的發生率低於未分級肝素，但由於低分子量肝素與標準未分級肝素之間的廣泛交叉反應（> 90%），因此不應將低分子量肝素用作這些患者的安全替代品。
LMWHs have been proposed to cause less bleeding and less thrombocytopenia than heparin. The LMWH dalteparin is used widely in European countries; however, the use of LMWHs for hemodialysis anticoagulation in the United States is very limited. While LMWHs have been demonstrated to be similarly safe and efficacious compared to UFH, it has generally not been found to be superior to heparin in terms of dialysis-related bleeding, and the increased cost may not justify the preferential use over UFH. It is also important to note that even though the incidence of HIT is lower than with UFH, LMWHs should not be used as a safe substitute in these patients because of the extensive cross-reactivity (> 90%) between LMWHs and standard UFH.

低分子量肝素（LMWHs）可以通過共價結合低分子量肝素到所有表面來降低體外循環本身的血栓生成性。初步研究顯示，這一策略可以安全使用而無需任何額外的藥物，但與區域性和無肝素策略相比，這種方法在預防血栓和出血方面的臨床和成本效益尚未被檢驗，並且在門診透析單位中並不容易獲得。
LMWHs can be used to decrease the thrombogenicity of the extracorporeal circuit itself by covalently coupling LMWH to all surfaces. Preliminary studies have shown that this strategy can be safely used without any additional agents, but the clinical and cost effectiveness of this approach to prevent thrombosis and bleeding compared to regional and no-heparin strategies has yet to be examined and is not readily available in outpatient dialysis units.

重組海盜素抗凝血
Recombinant Hirudin Anticoagulation

肝素直接結合並抑制凝血酶，通過形成非共價複合物（見圖 10.1）。重組肝素（lepirudin）可作為單次劑量在血液透析開始時給予，或作為持續輸注。Lepirudin 是一種有效的抗凝劑，並且可能導致的活化凝血時間（ACT）延長少於肝素。Lepirudin 主要由腎臟排泄，因此在血液透析患者中應謹慎使用，因為其延長的半衰期（> 35 小時）可能導致重複使用時出現出血併發症。沒有解毒劑可用於逆轉其抗凝效果。對於被診斷為肝素誘導的血小板減少症（HIT）的患者，建議使用 Lepirudin 作為替代的血液透析抗凝方法。它在門診透析單位也不易獲得。
Hirudin directly binds and inhibits thrombin via the formation of a noncovalent complex (see Fig. 10.1 ). Recombinant hirudin (lepirudin) has been administered either as a single bolus at the start of hemodialysis or as a continuous infusion. Lepirudin is an effective anticoagulant and may result in less prolongation of the ACT than heparin. Lepirudin is primarily excreted by the kidneys, and for this reason, it should be used carefully in hemodialysis patients, as its prolonged half-life (> 35 hours) may lead to bleeding complications with repetitive use. There is no antidote available to reverse its anticoagulant effects. Lepirudin is recommended as an alternative hemodialysis anticoagulation method in patients diagnosed with HIT. It is also not readily available in outpatient dialysis units.

阿加曲班   Argatroban

阿加曲班是一種直接的凝血酶抑制劑，源自於精氨酸，已獲得批准用於抗凝治療患有血小板減少症（HIT）或其他對肝素有禁忌症的患者的血液透析回路。阿加曲班可逆性地結合於催化凝血酶的活性位點，從而防止纖維蛋白的形成並抑制 V、VIII 和 XIII 因子的活化（見圖 10.1）。與重組的海盜素產品不同，阿加曲班主要在肝臟代謝；因此，對於肝病患者應謹慎使用。可作為初始劑量 100–250 μg/kg，隨後進行維持輸注 0.5–2 μg/kg/min，調整至 aPTT 為基線值的 1.5–3 倍。與大多數血液透析抗凝方法一樣，阿加曲班輸注應在治療結束前約 30 分鐘停止，以避免插管部位出現過度出血。阿加曲班通常僅限於住院使用。
Argatroban is a direct thrombin inhibitor derived from arginine approved for the anticoagulation of the hemodialysis circuit in patients diagnosed with HIT or with other contraindications to heparin. Argatroban reversibly binds to the catalytic thrombin active site, consequently preventing fibrin formation and inhibiting activation of factors V, VIII, and XIII (see Fig. 10.1 ). As opposed to recombinant hirudin products, argatroban is mainly metabolized by the liver; therefore, it should be used with caution in patients with liver disease. It can be given as an initial bolus of 100–250 μg/kg followed by a maintenance infusion of 0.5–2 μg/kg/min adjusted to an aPTT 1.5–3 times of the baseline value. As with most hemodialysis anticoagulation methods, argatroban infusion should be discontinued ~ 30 minutes before the end of therapy to avoid excessive bleeding from cannulation sites. Argatroban is usually reserved for in-hospital use.

肝素類：達那帕肝素和方多肝素
Heparinoids: Danaparoid and Fondoparinux

肝素類物質是從肝素衍生的糖胺聚糖。這些藥物作為血液透析抗凝的替代方法的經驗非常有限。達那帕羅德含有肝素硫酸鹽、真皮硫酸鹽和軟骨素硫酸鹽。與肝素類似，其抗凝效果主要是通過抑制 Xa 因子來介導（見圖 10.1）。達那帕羅德目前在美國不可用。對於監測，活化部分凝血酶時間（aPTT）並不有用，必須測量抗 Xa 因子活性。沒有可用的解毒劑。達那帕羅德含有類肝素化合物，並且在多達 10%的病例中報告了與肝素誘導的血小板減少症（HIT）抗體的交叉反應。
Heparinoids are glycosaminoglycans derived from heparin. The experience with these agents as an alternative method for hemodialysis anticoagulation is very limited. Danaparoid contains heparin sulfate, dermatan sulfate, and chondroitin sulfate. Similar to heparin, its anticoagulation effects are mainly mediated by inhibition of factor Xa (see Fig. 10.1 ). Danaparoid is currently not available in the United States. For monitoring, aPTT is not helpful, and anti–factor Xa activity has to be measured. There are no antidotes available. Danaparoid contains heparin-like compounds, and cross- reactivity with HIT antibodies has been reported in up to 10% of cases.

Fondoparinux 是一種五糖，亦可結合抗凝血酶，導致對活化因子 X 的間接抑制（見圖 10.1）。該藥物目前未獲批准用於血液透析抗凝，並且在末期腎病患者中應極為謹慎使用，因為其半衰期顯著延長，有時可能導致透析間期的全身抗凝。
Fondoparinux is a pentasaccharide that also binds to antithrombin, causing indirect inhibition of activated factor X (see Fig. 10.1 ). This agent is not currently approved for hemodialysis anticoagulation, and it should be used with extreme caution in end-stage kidney disease patients since the half-life is significantly increased, which at times can lead to interdialytic systemic anticoagulation.

區域性抗凝治療與魚精蛋白逆轉
Regional Anticoagulation With Protamine Reversal

最早描述的減少血液透析相關出血的方法是使用原子蛋白逆轉的區域性抗凝。此程序涉及將肝素持續輸注到透析器動脈管路（透析前），同時將中和劑原子蛋白持續輸注到靜脈（透析後）回路，以防止全身性抗凝（圖 10.2）。輸注泵的速率調整為保持透析器回路中的全血 ACT 在 250 秒，並使返回患者的血液保持在其透析前基線。由於技術困難以及在透析結束後 2 至 4 小時內原子蛋白-肝素複合物釋放自由肝素回到全身循環（導致反彈出血），原子蛋白逆轉已被大部分放棄。此外，隨後開發了更簡單的方案，包括最小劑量和無劑量肝素以及檸檬酸區域性抗凝，這些方案提供了較低的出血併發症發生率。
The earliest method described to reduce hemodialysis- associated bleeding was regional anticoagulation with protamine reversal. This procedure involves the constant infusion of heparin into the dialyzer arterial line (predialyzer), and the simultaneous constant infusion of the neutralizing agent, protamine, into the venous (post-dialyzer) limb of the circuit to prevent systemic anticoagulation ( Fig. 10.2 ). The infusion pump rates are adjusted to keep the whole blood ACT in the dialyzer circuit at 250 seconds and the blood returning to the patient at its predialysis baseline. Because of the technical difficulties and the release of free heparin from the protamine-heparin complex back into the general circulation 2 to 4 hours after the termination of dialysis (resulting in rebound bleeding), protamine reversal has been largely abandoned. In addition, simpler regimens consisting of minimum and no dose heparin as well as citrate regional anticoagulation have subsequently been developed that offer a lower incidence of bleeding complications.

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血液透析抗凝療法的示意圖，適用於出血風險增加的患者。
Schematic Representation of Hemodialysis Anticoagulation Modalities for Patients at Increased Risk of Bleeding.

所描繪的方式為 (1) 無肝素/生理鹽水沖洗；(2) 區域性肝素抗凝加上原蛋白逆轉；以及 (3) 區域性檸檬酸抗凝。
The modalities depicted are (1) no heparin/saline flush; (2) regional heparin anticoagulation with protamine reversal; and (3) regional citrate anticoagulation.

區域檸檬酸抗凝血
Regional Citrate Anticoagulation

在許多機構中採用的區域檸檬酸方案涉及將等滲的三鈉檸檬酸溶液（102 mmol/L）持續輸注到透析器的動脈肢體。檸檬酸與鈣形成螯合物，是凝血級聯反應中不同步驟所需的關鍵輔因子（見圖 10.1）。由於與檸檬酸結合而導致的游離血漿鈣濃度下降，防止了體外循環中凝血級聯反應的進展。使用無鈣透析液，然後通過透析器去除部分檸檬酸-鈣複合物。檸檬酸的輸注速率調整以保持動脈肢體的 ACT 高於 200 秒。通過以 0.5 mL/min 的速率將 5%氯化鈣輸注到靜脈回流管中來實現正常鈣血症和區域抗凝。這一速率根據頻繁測量的血漿鈣濃度不斷調整，以防止低鈣血症或高鈣血症。這項技術的修改使用高滲的三鈉檸檬酸（1.6 mol/L）和含有 3 mEq/L 鈣的透析液，以期最小化通過靜脈輸注所需的替代鈣量（見圖）。 10.2 ). 柠檬酸在肝臟中轉化為碳酸氫鹽，這可能導致代謝性鹼中毒，特別是在與持續性腎替代療法（CRRT）一起使用時。因此，建議使用較低濃度碳酸氫鹽的透析液。有時，代謝性鹼中毒的程度嚴重到需要用鹽酸輸注進行治療。
The regional citrate regimen that has been adopted in many institutions involves the continuous infusion of isosmotic trisodium citrate solution (102 mmol/L) into the arterial limb of the dialyzer. Citrate chelates calcium is a key cofactor required for different steps in the coagulation cascade (see Fig. 10.1 ). The fall in the free plasma calcium concentration induced by binding to citrate prevents the progression of the coagulation cascade in the extracorporeal circuit. A calcium-free dialysate is used and some of the citrate-calcium complex is then removed across the dialyzer. The citrate infusion rate is adjusted to keep the ACT above 200 seconds in the arterial limb. Normocalcemia and regional anticoagulation is achieved by the infusion of 5% calcium chloride into the venous return line at a rate of 0.5 mL/min. This rate is constantly adjusted according to frequent measurements of plasma-calcium concentration to prevent hypocalcemia or hypercalcemia. A modification of this technique utilizes hypertonic trisodium citrate (1.6 mol/L) and dialysate containing 3 mEq/L of calcium in an attempt to minimize the amounts of replacement calcium needed via venous infusion (see Fig. 10.2 ). Citrate is converted to bicarbonate in the liver, which may lead to metabolic alkalosis, especially when used with CRRT. For this reason, it is recommended to use a dialysate with a lower concentration of bicarbonate. At times, the metabolic alkalosis is severe enough to require treatment with a hydrochloric acid infusion.

比較試驗顯示，與標準肝素方案相比，使用檸檬酸鹽基方案的出血發生率降低，因此建議作為高出血風險患者的替代方法。除了技術複雜性和監測強度外，區域性檸檬酸抗凝的主要問題是低鈣血症、高鈣血症、高鈉血症（由於高滲透鈉檸檬酸鹽溶液）和代謝性鹼中毒（由於檸檬酸在肝臟代謝過程中產生的碳酸氫根）。肝功能不全的患者特別容易出現代謝性併發症。檸檬酸輸注也可能影響血液中細胞成分的功能，包括白血球活化和血小板功能，這是由於其低鈣血症效應。然而，如果進行密切監測，併發症的發生率相對較低。這種方法主要保留用於住院使用。
Comparative trials have shown a reduced incidence of bleeding with citrate-based regimens compared to standard heparin protocols, so it is recommended as an alternative method for patients with high bleeding risk. Apart from technical complexity and the intensity of monitoring, the major problems with regional citrate anticoagulation are the possibility of hypocalcemia, hypercalcemia, hypernatremia (due to the hypertonic sodium citrate solution), and metabolic alkalosis (due to bicarbonate generated during hepatic metabolism of citrate). Patients with liver insufficiency are especially at risk for metabolic complications. Citrate infusion can also affect the function of cellular elements of the blood, including leukocyte activation and platelet function via its hypocalcemic effects. If closely monitored, however, the complication rate is relatively low. It is mostly reserved for in-hospital use.

前列腺素 C1 區域抗凝血療法
Prostacyclin Regional Anticoagulation

花生四烯酸代謝物前列腺素 I2 是一種血管擴張劑和血小板聚集抑制劑。其體外半衰期為 3 至 5 分鐘，因為內皮平滑肌的快速代謝。前列腺素 I2 區域抗凝涉及以每分鐘 4 至 8 ng/kg 的劑量將前列腺素 I2 注入透析器回路。由於其不利的副作用，包括頭痛、頭暈、面部潮紅、因血管擴張引起的低血壓以及成本，這種方法很少被推薦。
The arachidonic metabolite prostacyclin is a vasodilator and inhibitor of platelet aggregation. Its in vitro half-life is 3 to 5 minutes due to rapid metabolism by endothelial-smooth muscle. Prostacyclin regional anticoagulation involves the infusion of prostacyclin into the dialyzer circuit at 4 to 8 ng/kg per minute. This method is rarely recommended due to its unfavorable side-effect profile, including headache, lightheadedness, facial flushing, hypotension due to vasodilation, and cost.

納法莫司是一種前列腺素類似物，與較少的血壓不良反應相關，但在美國尚未上市。然而，它可能與不可接受的高血栓形成率相關。在一項使用納法莫司的研究中，儘管適當延長了活化部分凝血酶時間（aPTT），仍觀察到高達 36%的透析器出現血栓形成。此外，納法莫司不能與聚丙烯腈膜一起使用，因為會吸附在膜表面。
Nafamostat is a prostacyclin analog associated with fewer adverse effects on blood pressure but is not yet available in the United States. It may, however, be associated with an unacceptably high incidence of clot formation. In one study using nafamostat, clot formation was observed in up to 36% of dialyzers despite adequate prolongation of the aPTT. In addition, nafamostat cannot be used with polyacrylonitrile membranes due to adsorption onto the membrane surface.

無肝素透析   Heparin-Free Dialysis

在患者出現出血風險增加的情況下，抗凝治療在血液透析期間變得具有挑戰性。對於這些高風險患者，已使用多種替代療法，例如低劑量肝素或區域性抗凝。然而，這些策略仍然存在出血風險，可能高達 50%。區域性檸檬酸抗凝的使用通常僅限於住院單位或特定指定的門診單位。因此，在出血風險增加或有活動性出血的患者中，無肝素血液透析是首選的抗凝方法。這對於有肝素誘導的血小板減少症（HIT）或其他肝素禁忌症的患者也是合理的替代方案。在此方案中，透析器和管路預處理 2000 至 5000 IU 的肝素，溶於 1 升生理鹽水中，或者（特別是在 HIT 患者中）僅使用生理鹽水。在肝素化生理鹽水預處理的情況下，體外循環在透析治療開始之前僅用生理鹽水沖洗，以確保不將肝素給予患者。 體外血流迅速增加至 250–500 mL/min，並在整個治療過程中維持，並每 15 至 30 分鐘在動脈（透析前）肢體中注入 25 至 30 mL 的生理鹽水沖洗，以最小化血液濃縮並將纖維蛋白絲從透析器沖洗到氣泡捕集器中。值得注意的是，注入的生理鹽水體積必須計入透析過程中的超濾目標，以防止體積過載。進行生理鹽水沖洗的過程中需要一對一護理，並仔細監測動脈和靜脈壓力警報，以便及早發現體外循環的血栓形成。
In circumstances where patients are at increased risk of bleeding, the use of anticoagulation becomes challenging during hemodialysis. A number of alternative modalities have been used in these at-risk patients, such as low-dose heparin or regional anticoagulation. However, there is still an associated risk of bleeding with these strategies, which can be as high as 50%. The use of regional citrate anticoagulation is generally restricted to inpatient units or specifically designated outpatient units. Therefore, in patients with increased bleeding risk or active bleeding, no-heparin hemodialysis is the preferred method of anticoagulation. This is also a reasonable alternative for patients with HIT or other contraindications to heparin. In this protocol, the dialyzer and tubing are pretreated with 2000 to 5000 IU of heparin contained in 1 L of normal saline or, alternatively (especially in HIT patients), just saline. In the case of heparinized saline pretreatment, the extracorporeal circuit is flushed with saline alone prior to the start of the dialysis treatment so that heparin is not administered to the patient. Extracorporeal blood flows are rapidly increased to 250–500 mL/min and maintained throughout the treatment with 25 to 30 mL saline flushes administered every 15 to 30 minutes into the arterial (predialyzer) limb to minimize hemoconcentration and to wash fibrin strands from the dialyzer into the bubble trap. Of note, the volume of saline administered must be added to the ultrafiltration goal during dialysis to prevent volume overload. One-on-one nursing is required for administration of saline flushes and careful monitoring of the arterial and venous pressure alarms to detect early extracorporeal circuit clotting.

使用這種技術，約 90%的有出血風險增加且需要血液透析的重症監護病房（ICU）患者可以成功透析，體外循環中的凝血率僅為 2%。與接受標準抗凝治療的患者相比，未報告明顯的清除率損失。在約 5%的案例中，需要轉換為最低劑量的肝素或停止治療。
Using this technique, about 90% of intensive care unit (ICU) patients with increased risk of bleeding who require hemodialysis can be successfully dialyzed with only a 2% clotting rate in the extracorporeal circuit. No significant loss of clearances has been reported compared to patients on standard anticoagulation. In approximately 5% of the cases, conversion to minimum-dose heparin or treatment discontinuation is required.

這種技術的缺點包括為了維持體液狀態而需要增加的超濾速率，這可能促進低血壓並增加透析器回路的凝血和血栓形成。無肝素技術的另一個問題是，由於凝血風險增加，通常無法通過透析器回路進行輸血，這可能對周邊血管通路有限的患者造成困難。一個潛在的解決方案是成功使用大口徑的止回閥將血液輸注到回路的靜脈肢體（透析後）。另一個缺點是需要增加的工作人員時間進行密切觀察，這可能會提高透析成本。基於這些原因，無肝素策略不建議作為門診血液透析的長期抗凝治療。
The disadvantages of this technique include the associated increased ultrafiltration rate required to maintain volume status, which can promote hypotension and increase dialyzer circuit clotting and thrombosis. An additional problem with the no-heparin technique is that blood transfusions cannot usually be given through the dialyzer circuit due to the increased risk of clotting, which may pose difficulty for patients with limited peripheral access. A potential solution, which has been successfully used, is to utilize a large-bore stopcock to transfuse blood into the venous limb (postdialyzer) of the circuit. Another disadvantage is the increased staff time needed for close observation, which can potentially elevate dialysis costs. For these reasons, no-heparin strategies are not recommended as a long-term anticoagulation therapy for outpatient hemodialysis.

肝素接枝透析器   Heparin-Grafted Dialyzer

另一種無肝素血液透析的替代方案是使用肝素接枝的透析器，這些透析器已成功單獨使用（不需生理鹽水沖洗）或與檸檬酸增強的透析液結合使用。這些透析器的表面塗有能夠結合肝素的物質。與這些透析器相關的凝血率似乎在 15%到 30%之間。初步研究表明，肝素接枝透析器在效果上不劣於目前的標準無肝素透析，使用簡便，並且對於高出血風險的患者來說，代表了一個合理的血液透析抗凝選擇，但目前並不容易獲得。
Another alternative to no-heparin hemodialysis is the use of heparin-grafted dialyzers, which have been successfully used alone (without saline flushes) or in combination with a citrate-enriched dialysate. These dialyzers are coated with a substance that binds heparin. The clotting rate associated with these dialyzers seems to be between 15% and 30%. Preliminary studies suggest that heparin-grafted dialyzers are noninferior to current standard heparin-free dialysis, are easy to use, and represent a reasonable choice for hemodialysis anticoagulation in patients with high bleeding risk but are not readily available.

檸檬酸透析液   Citrate Dialysate

類似於區域檸檬酸抗凝，這一策略利用檸檬酸的鈣抑制作用來阻止凝血級聯反應中的不同步驟（見圖 10.1）。檸檬酸增強的透析液取代了通常用於酸化的醋酸，使用相對低濃度的檸檬酸（2.4 mEq/L，0.8 mmol/L）。這導致在體外循環中局部減少血塊形成，使透析治療可以不使用或僅使用非常低劑量的肝素進行抗凝。重要的是，檸檬酸透析液能夠降低血清鈣濃度，足以干擾凝血級聯反應，但不足以引起有症狀的低鈣血症。因此，與區域檸檬酸抗凝不同，鈣的補充並不是必要的。
Similar to regional citrate anticoagulation, this strategy utilizes the calcium inhibiting effects of citrate to block different steps in the coagulation cascade (see Fig. 10.1 ). The citrate-enriched dialysate replaces the acetate normally used for acidification, utilizing citric acid at a relatively low concentration (2.4 mEq/L, 0.8 mmol/L). This results in reduced clot formation locally in the extracorporeal circuit, allowing a dialysis treatment with either no or only a very low dose of heparin for anticoagulation. Importantly, citrate dialysate lowers serum calcium sufficiently to interfere with the clotting cascade, but not enough to cause symptomatic hypocalcemia. Thus, calcium replacement is not necessary, as opposed to regional citrate anticoagulation.

在患有 HIT 的病人中使用導管鎖
Catheter Lock in Patients With HIT

在有血小板減少症（HIT）的患者中，血液透析導管的鎖定選擇包括使用壓力袋對導管進行鎖定（這對於門診病人來說不切實際）或注入組織纖溶酶原激活劑或尿激酶。高濃度（47%）的檸檬酸也被使用，但由於意外全身注射導致心律不整的問題，尚未獲得食品藥品監督管理局的批准。使用較低濃度檸檬酸溶液（4%至 7%）的研究表明，這一策略在維持血液透析導管的長期透析間隙通暢性方面是安全且同樣有效的。一項使用 30%檸檬酸鎖定溶液的研究發現不良事件沒有增加，並且與標準肝素鎖定溶液相比，導管相關的菌血症風險降低。
Hemodialysis catheter lock options in patients with HIT are to pressure bag the catheters (which is impractical for outpatients) or instill either tissue plasminogen activator or urokinase. Highly concentrated (47%) citrate has also been used but is not Food and Drug Administration approved due to issues of accidental systemic injection with resulting arrhythmias. Studies with lower concentration citrate solutions (4% to 7%) indicate that this strategy is safe and similarly effective for the maintenance of long-term interdialytic patency of hemodialysis catheters. A study using a 30% citrate locking solution found no increase in adverse events and also found a decreased risk of catheter- related bacteremia compared to a standard heparin locking solution.