2024年7月10日 (三) 18:11的最后版本

原文：https://pubmed.ncbi.nlm.nih.gov/10476710/

发表于：1999

溴鼠灵 (Brodifacoum) 又名溴联苯鼠隆、大隆。为第二代抗凝血杀鼠剂，是抗凝血剂中毒性最大的一种，具有急性和慢性杀鼠剂的双重优点。适口性好，不会产生拒食作用，可杀死对第一代抗凝血剂产生抗性的鼠类。对家畜、家禽等剧毒，对鱼类有微毒。防治田间野鼠，每亩投饵10-15堆，每堆5一7克。或沿田埂、地垅设置毒饵，每5米布一饵点，每个饵点投药5克。防治达乌尔黄鼠、家鼠等，可投于洞谤，每洞投药7－10克。

[编辑] 1 摘要

摄入抗凝剂灭鼠剂导致的出血可能在任何创伤部位或任何体腔中都很明显。对于临床医生来说，在进行常规心包穿刺术之前，将凝血病纳入心包积液的鉴别诊断中，并评估凝血功能非常重要。

Hemorrhage resulting from ingestion of anticoagulant rodenticides may be evident at any traumatized site or in any body cavity. It is important for clinicians to include coagulopathies among the differential diagnoses for pericardial effusion and to evaluate clotting function before routine pericardiocentesis is performed.

[编辑] 2 正文

一只 7 岁的 33.6 公斤（74-1b）绝育雌性德国 L Wirehaired Pointer 被转诊到我们的兽医教学医院进行紧急评估和治疗。这只狗在进入我们设施前的 2 天内多次倒下并出现呼吸急促。转诊兽医在入院当天早些时候进行的胸 X 线摄影显示全身性心脏肥大和斑片状肺泡模式。在转诊兽医进行的其他检查中，全血细胞计数显示白细胞增多可归因于成熟的中性粒细胞增多症，但血清生化分析结果无明显异常，检测心丝虫抗原的检测结果为阳性。

体格检查显示，这只狗昏昏欲睡，粘膜苍白、发粘。呼吸费力且急促（60 次呼吸/分钟）。听诊发现双侧湿啰音和喘息音，心音模糊。股动脉搏动微弱且不规则，未检测到颈静脉搏动。未见小出血或瘀斑性出血的证据。

最初的诊断工作包括心电图，显示心率为160次/分钟的窦性心动过速，但我们没有检测到异位搏动或复杂振幅或硬度的异常。为评估转诊兽医拍摄的 X 线片上明显的心脏扩大而进行的超声心动图显示，严重的心包积液导致薄壁右心房塌陷（即心包填塞）。心肌功能被认为是正常的，而提示血管肉瘤或血管瘤是积液原因的肿块并不明显。

A 7-year-old 33.6-kg (74-1b) spayed female German L Wirehaired Pointer was referred to our veterinary medical teaching hospital for emergency evaluation and treatment. The dog had collapsed repeatedly and was tachypneic during the 2 days preceding admission to our facility. Thoracic radiography performed by the referring veterinarian earlier on the day of admission revealed generalized cardiomegaly and a patchy alveolar pattern. In other testing performed by the referring veterinarian, a CBC revealed leukocytosis attributable to mature neutrophilia, but results of serum biochemical analyses were unremarkable, and results of a test to detect heartworm antigens were positive.

Physical examination revealed the dog was lethargic and had pale, tacky mucous membranes. Breathing was labored and rapid (60 breaths/min). Auscultation revealed crackles and wheezes bilaterally, and heart sounds were muffled. Femoral pulses were weak and irregular, and jugular pulses were not detected. Evidence of petechiation or ecchymotic hemorrhages was not seen.

Initial diagnostic efforts consisted of electrocardiography, which revealed sinus tachycardia with a heart rate of 160 beats/min, but we did not detect ectopic beats or abnormalities of complex amplitude or dura-tion. Echocardiography performed to evaluate the cardiomegaly evident on the radiographs taken by the referring veterinarian revealed severe pericardial effusion causing collapse of the thin-walled right atrium (ie, cardiac tamponade). Myocardial function was considered to be normal, and masses that would have suggested hemangiosarcoma or chemodectoma as the cause of the effusion were not evident.

确定需要心包穿刺术来降低心包压并增加心脏充盈和输出量。由于该狗在检测心丝虫抗原的测试中呈阳性结果，因此弥散性血管内凝血 （DIC） 被认为是心包积液的可能原因。活化凝血时间延长（267秒;参考范围，<120秒）。入院时PCV为36%，而一天前为52%。为了调查活化凝血时间延长的原因，进行了凝血功能测试。一级凝血酶原时间（OSPT）为32.7秒（混合血浆对照样品的值为7.4秒），活化部分凝血活酶时间（APTT）为36.0秒（对照样品，11.3秒），纤维蛋白降解产物（FDP）浓度为10至40 ug/ml（参考范围，<10 g/ml），纤维蛋白原浓度为420 mg/dl（对照样品，157 mg/di）。血涂片检查显示血小板数量充足。

在将初步实验室结果传达给主人后，对狗的环境进行了灭鼠剂搜索。在业主的车库里发现了一盒部分食用的含有活性成分溴鼠灵 (Brodifacoum) 的抗凝血灭鼠剂。

初始治疗包括给予维生素 K1（2.5 mg/kg [1.1 mg/lb] 体重，SC）和静脉给予乳酸林格溶液和 1 U 新鲜全血。给予新鲜全血以恢复血容量并立即补充凝血因子，因为在肠胃外给予维生素 K 后需要 6 至 12 小时，然后才能合成临床上大量的凝血因子。输血后，狗的昏昏欲睡较少，但它仍然出现呼吸困难和呼吸急促，尽管心率在参考范围内。

狗的状况在一夜之间保持稳定，并在第二天早上重复进行凝血测试。入院后约 12 小时，OSPT 为 13 秒，APTT 为 21.5 秒。

由于心包填塞仍然明显，因此进行了心包穿刺术。心包囊的渗透导致液体渗出到胸膜腔中;未取回心包液进行细胞学 IC 分析。心包穿刺术后进行的胸 X 线摄影显示胸膜裂线与流入胸膜腔的心包液一致。轻度心脏扩大和支气管间质模式与肺出血或误吸相符也很明显。

心包穿刺术后，心电图显示短暂性二度房室传导阻滞，随后出现阵发性室性心动过速。给予2%盐酸利多卡因溶液后室性心动过速消退（2.2 mg/kg（1 mg/lbl，静脉注射，一次）;然而，随后出现心房颤动。给狗服用奎尼丁（12 mg/kg （5.4 mg/b），PO，每 8 小时一次），并在奎尼丁给药后 2 小时将心房颤动转化为窦性心律。在接下来的 48 小时内连续进行心电图检查，但未检测到其他心律失常。

It was determined that pericardiocentesis was needed to decrease intrapericardial pressure and increase cardiac filling and output. Because the dog had positive results on a test to detect heartworm antigen, disseminated intravascular coagulation (DIC) was considered a possible cause of the pericardial effusion. Activated clotting time was prolonged (267 seconds; reference range, < 120 seconds). The PCV was 36% at the time of admission, compared with 52% one day earlier. To investigate the reason for the prolonged activated clotting time, coagulation profile testing was performed. One-stage prothrombin time (OSPT) was 32.7 seconds (value for pooled plasma control sample, 7.4 seconds), activated partial thromboplastin time (APTT) was 36.0 seconds (control sample, 11.3 seconds), concentration of fibrin degradation products (FDP) was between 10 and 40 ug/ml (reference range, < 10 g/ml), and fibrinogen concentration was 420 mg/dl (control sample, 157 mg/di). Examination of a blood smear revealed that there was an adequate number of platelets.

After initial laboratory results were conveyed to the owners, the dog's environment was searched for rodenticides. A partially eaten box of an anticoagulant rodenticide containing the active ingredient brodifa-coum was discovered in the owners' garage.

Initial treatment consisted of administration of vitamin K1 (2.5 mg/kg [1.1 mg/lb] of body weight, SC) and IV administration of lactated Ringer solution and 1 U of fresh whole blood. Fresh whole blood was administered to restore blood volume and immediately replace clotting factors, because it requires 6 to 12 hours after parenteral administration of vitamin K, before clinically substantial amounts of clotting factors are synthesized.' After the transfusion, the dog was less lethargic, but it was still dyspneic and tachypneic, although heart rate was within the reference range.

The dog's condition remained stable overnight, and coagulation tests were repeated on the subsequent morning. Approximately 12 hours after admission, OSPT was 13 seconds and APTT was 21.5 seconds.

Because cardiac tamponade was still evident, peri-cardiocentesis was performed. Penetration of the pericardial sac resulted in exudation of fluid into the pleural space; pericardial fluid was not retrieved for cytolog-ic analysis. Thoracic radiography performed after pericardiocentesis revealed pleural fissure lines consistent with pericardial fluid that had drained into the pleural space. Mild cardiomegaly and a bronchointerstitial pattern consistent with pulmonary hemorrhage or aspiration also were evident.

After pericardiocentesis, electrocardiography revealed transient second-degree atrioventricular block followed by paroxysmal ventricular tachycardia. Ventricular tachycardia resolved after administration of a 2% solution of lidocaine hydrochloride' (2.2 mg/kg (1 mg/lbl, IV, once); however, atrial fibrillation then developed. The dog was given quinidine (12 mg/kg (5.4 mg/b], PO, q 8 h), and the atrial fibrillation converted to sinus rhythm 2 hours after quinidine admin-istration. Electrocardiography was performed continuously for the next 48 hours, but additional arrhythmias were not detected.

维生素 K1 口服给药，剂量为 0.75 mg/kg （0.34 mg/b），第一周每 8 小时一次，之后降至 0.75 mg/kg，每 12 小时一次，持续 3 周。在进入兽医教学医院后的第三天，超声心动图未发现心包积液或心室功能障碍的证据，狗出院了。重复了检测心丝虫抗原的测试，但第二次测试的结果为阴性。完成维生素 K1 治疗后 2 天和 7 天进行的 OSPT 结果在可接受的范围内。事件发生一年后，主人报告说这只狗状况良好。用于检测心丝虫的后续测试（每年进行一次）的结果为阴性。

据我们所知，这是首次报告犬继发于摄入抗凝剂灭鼠剂而引发心包积液。然而，在一项对 10 只被第二代抗凝剂毒害的动物的回顾性研究[1]中，在尸检期间在 1 只狗中发现心包积血[2] 在接受抗凝剂治疗的人中已有心包积液的报道。[3-5] 犬大量心包积液的其他不同诊断包括心脏肿瘤、特发性心包炎和外伤。较少见的是，感染性心包炎、充血性心力衰竭、左心房撕裂和先天性缺陷（如腹膜心包膈疝）也可能导致心包积液。[6] 评估心包积液的常规诊断程序包括胸 X 线摄影、心电图和超声心动图。由于心包积液可能会使薄壁右心房和右心室塌陷，并干扰舒张期充盈，因此心包穿刺术适用于患者的初始血流动力学稳定。[6] 在此报道的狗中，心包穿刺术前的凝血功能评估对于确定诊断以及指示初始治疗至关重要，因为心包穿刺术可能导致额外的出血。

凝血功能障碍可能由抗凝血杀鼠剂、DIC、肝脏尾部和先天性凝血因子的敏感性引起。[7] 在此报告的狗中，DIC 被认为不太可能，因为在血涂片检查时估计有足够数量的血小板，纤维蛋白原浓度大于对照样本的浓度，并且 FDP 浓度仅轻度增加。在少数抗凝剂灭鼠剂中毒病例中观察到 FDP 浓度轻度增加，可能是由于外渗血纤维蛋白溶解增加所致。

血清生化分析结果不支持肝病的诊断。因为在卵巢子宫切除术时大量出血并不明显，而且狗对维生素 K1 给药反应良好，所以先天性凝血因子缺乏似乎不太可能。杀鼠剂诱导的抗共凝血功能得到以下因素的支持：溴敌粪暴露史、诊断性试验结果、对凝血因子替代和维生素 K1 给药的反应，以及在此发作后随后的完全恢复。

Oral administration of vitamin K1 was instituted at a dosage of 0.75 mg/kg (0.34 mg/b), every 8 hours for the first week, after which it was decreased to 0.75 mg/kg, every 12 hours for 3 additional weeks. On the third day after admission to the veterinary medical teaching hospital, echocardiography did not reveal evidence of pericardial effusion or ventricular dysfunc-tion, and the dog was discharged. The test to detect heartworm antigen was repeated, but the results of that second test were negative. Results of OSPT conducted 2 and 7 days after completing treatment with vitamin K1 were within acceptable limits. One year after this episode, the owners reported that the dog was doing well. Results of subsequent tests (performed annually) to detect heartworms have been negative.

To our knowledge, this is the first report of pericardial effusion secondary to ingestion of anticoagulant rodenticides in a dog. However, in a retrospective study[1] of 10 animals poisoned with second-generation anticoagulants, hemopericardium was found in 1 dog during necropsy[2] Pericardial effusion has been reported in people treated with anticoagulants.[3-5] Other diffterential diagnoses for substantial pericardial effusion in dogs include cardiac neoplasms, idiopathic pericarditis, and trauma. Less commonly, infectious pericarditis, congestive heart failure, tears in the left atrium, and congenital defects such as peritoneal pericardial diaphragmatic hernia may also cause pericardial effusion.[6] Routine diagnostic procedures for the evaluation of pericardial effusion include thoracic radiography, electrocardiography, and echocardiography. Because pericardial effusion may collapse the thin-walled right atrium and right ventricle and interfere with diastolic filling, pericardiocentesis is indicated for initial hemodynamic stabilization of patients.[6] In the dog reported here, evaluation of clotting function prior to pericardiocentesis was essential for establishing the diagnosis as well as indicating initial management, because additional hemorrhage may have resulted from pericardiocentesis.

Coagulopathy may be caused by anticoagulant rodenticides, DIC, liver tailure, and congenital deli-ciencies of clotting factors.[7] In the dog reported here, DIC was considered unlikely because of an estimate of a sufficient number of platelets on examination of a blood smear, fibrinogen concentration that was greater than the concentration of a control sample, and only a mild increase in FDP concentration. Mild increases in FDP concentration have been observed in a few cases of anticoagulant rodenticide toxicosis, possibly as a result of increased fibrinolysis of extravasated blood.

Results of a serum biochemical analysis did not support a diagnosis of hepatic disease. Because substantial bleeding had not been evident at the time of ovario-hysterectomy, and the dog responded well to vitamin K1 administration, congenital deficiencies of clotting factors seemed unlikely. Rodenticide-induced antico-agulation was supported by the history of brodifacoum exposure, results of diagnostic tests, response to replacement of clotting factors and administration of vitamin K1, and subsequent complete recovery after this episode.

溴鼠灵 (Brodifacoum) 是第二代抗凝剂，与华法林相比，具有更高的效力和更长的作用持续时间。虽然出血可能从任何创伤部位可见，但常见于腹膜、胃肠道、胸膜腔和肺实质马。尽管我们报告中的狗似乎存在肺出血，但心包积液导致的心包填塞似乎是凝血功能障碍的最严重后果。

心包穿刺术后出现的心律失常（二度房室传导阻滞、室性心动过速和心房颤动）可能有多种原因，但所有原因都可能继发于心脏创伤。由于心律失常在心包穿刺术之前并不明显，因此认为在心包穿刺术期间导管的直接心肌刺激最有可能引起我们报告的狗的心律失常。或者，迷走神经张力的突然变化或缺氧可能有助于心律失常的发生。

据信，转诊兽医使用的检测心丝虫抗原的测试提供了假阳性结果。在进入我们的设施时，这只狗已经每月进行心丝虫通气前治疗，并且没有任何与心丝虫疾病相符的放射学变化。此外，所有后续检测心丝虫抗原的检测结果均为阴性。患有溴敌菌中毒的动物的预后良好，只要尽量减少对动物的创伤并及时提供维生素K1。

对于严重出血的动物，也可能需要补充凝血因子。该报告说明了临床医生需要在心包穿刺术前评估凝血功能，因为患有溴鼠灵 (Brodifacoum) 中毒症的狗可能会因出血而产生大量心包积液。

Brodifacoum is a second-generation anticoagulant developed to have an increased potency and prolonged duration of action, compared to warfarin. Although hemorrhage may be evident from any traumatized site, it is commonly encountered in the peritoneum, gastrointestinal tract, pleural cavity, and lung parenchy-ma. Although there appeared to be pulmonary hemorrhage in the dog of our report, cardiac tamponade resulting from pericardial effusion appeared to be the most serious consequence of the coagulopathy.

Arrhythmias seen after pericardiocentesis (sec-ond-degree atrioventricular block, ventricular tachy-cardia, and atrial fibrillation) each may have a number of causes, but all may be seen secondary to cardiac trauma." Because arrhythmias were not evident prior to pericardiocentesis, it was believed that direct myocardial irritation by the catheter during pericar-diocentesis most likely caused arrhythmias in the dog of our report. Alternatively, sudden changes in vagal tone or hypoxia may have contributed to the development of arrhythmias.

It was believed that the test to detect heartworm antigen used by the referring veterinarian provided a false-positive result. At the time of admission to our facility, the dog had been on monthly heartworm pre-ventative, and there were not any radiographic changes consistent with heartworm disease. Furthermore, results of all subsequent tests to detect heartworm antigen were negative. Prognosis for animals with brodifacoum toxicosis is good providing trauma to the animal is minimized and vitamin K1 is provided in a timely manner.

Replacement of clotting factors may also be necessary in animals with severe hemorrhage. This report illustrates the need for clinicians to evaluate coagulation function prior to pericardiocentesis, because there may be substantial amounts of pericardial eflusion as a result of hemorrhage in dogs with brodifacoum toxicosis.

[编辑] 3 Referenece

• [1]. Murphy MJ, Gerken DE The anticoagulant rodenticides. In: Kirk RW, Bonagura JD, eds. Current veterinary therapy X. Philadelphia: WB Saunders Co, 1989;143-146.
• [2]. Duvall MD, Murphy MJ, Ray AC, et al. Case studies on sec-ond-generation anticoagulant rodenticide toxicities in nontarget species. J Vet Diagn Invest 1989;1:66-68.
• [3]. Granot H, Shinar E. Spontaneous anticoagulant-induced hemopericardium with tamponade. Acta Haemotol 1982;68:339-340.
• [4]. Lee KS, Marwick T. Hemopericardium and cardiac tampon-ade associated with warfarin therapy. Cleve Clin J Med 1993;60:336-338.
• [5]. Miller RL. Hemopericardium with the use of anticoagulant therapy: JAMA 1969;209:1362-1363.
• [6]. Miller MW, Sisson DD. Pericardial disorders. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 4th ed. Philadelphia: WB Saunders Co, 1995;1032-1045.
• [7]. Green RA, Thomas JS. Hemostatic disorders: coagu-lopathies and thrombosis. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 4th ed. Philadelphia: WB Saunders Co, 1995;1946-1963.
• [8]. Lunney J, Ettinger SJ. Cardiac arrhythmias. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 4th ed. Philadelphia: WB Saunders Co, 1995;959-995.

• 2000: 犬血管肉瘤的治疗：2000 年及以后兽医内科杂志 Treatment of canine hemangiosarcoma: 2000 and beyond. Journal of Veterinary Internal Medicine 2000
• 2010: 狗的胸腔镜次全心包切除术和右心房肿块切除术 Thoracoscopic subtotal pericardiectomy and right atrial mass resection in a dog
• 2013: 狗狗原发性心脏血管肉瘤的流行病学、临床和病理特征：51例的回顾。兽医学杂志 Epidemiological, clinical and pathological features of primary cardiac hemangiosarcoma in dogs: a review of 51 cases.
• 2014: 阿霉素化疗治疗狗的推定性心脏血管肉瘤 Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs
• 2014: 基于多柔比星的化疗对右心房肿块和心包积液狗的回顾性评估 A retrospective evaluation of doxorubicin-based chemotherapy for dogs with right atrial masses and pericardial effusion
• 2017: 多柔比星-环磷酰胺与多柔比星-达卡巴嗪辅助治疗犬血管肉瘤的比较 Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for HSA
• 2018: 犬内脏血管肉瘤单独手术治疗或手术加多柔比星治疗：37例（2005-2014年） Canine visceral hemangiosarcoma treated with surgery alone or surgery and doxorubicin: 37 cases (2005–2014)

• Nutritional Management of Patients with Neoplasia 小动物肿瘤患者的营养管理
• 狗狗心包积液