The therapeutic effects of hemoperfusion in treating long-acting anticoagulant rodenticide poisoning

The therapeutic effects of hemoperfusion in treating long-acting anticoagulant rodenticide poisoning | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 1 July 2025 V1 Latest version Share on The therapeutic effects of hemoperfusion in treating long-acting anticoagulant rodenticide poisoning Authors : Dong Jianguang , Wu Jieyi , Yin Bingling 0009-0008-4832-3817 , Peng Xiaobo , Lu Xiaoxia , Liu Zhongying , Fan Haojun , Liu Ziquan , Qiu Zewu , Wen Qiang , Pan Zhiguo , and Lin Guodong 0000-0001-5978-6288 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175135204.44451034/v1 227 views 79 downloads Contents Abstract Methods Results Trends in blood rodenticide concentrations Discussion Conclusion Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Introduction: Second-generation anticoagulant rodenticides often cause severe bleeding, which can be life-threatening with limited effective treatment options. This study aimed to evaluate the therapeutic efficacy of hemoperfusion in patients with rodenticide poisoning. Methods: This study conducted a retrospective analysis of 148 patients diagnosed with rodenticide poisoning at the Fifth Medical Center of the Chinese PLA General Hospital between 2014 and 2021. The patients were divided into two groups based on whether they received blood purification treatment. The clinical characteristics, serum drug concentrations, duration of hospital stay, and duration of vitamin K1 (VK1) therapy were compared between the two groups using univariate and multivariate analyses. Subgroup analyses were also conducted to assess the effect of hemoperfusion in patients poisoned with brodifacoum and bromadiolone. Results: This retrospective study included 115 patients hospitalized for rodenticide poisoning. The patients were divided into a hemoperfusion group (24 patients) and a non-hemoperfusion group (91 patients). The hemoperfusion group demonstrated a faster reduction in serum drug concentration. The subgroup analysis revealed that hemoperfusion significantly reduced the duration of VK1 therapy in patients poisoned with brodifacoum (P=0.044). Conclusion: Hemoperfusion effectively reduced serum rodenticide concentrations in patients with poisoning. Moreover, the subgroup analysis suggested that hemoperfusion can reduce the duration of VK1 therapy in patients with brodifacoum poisoning. The therapeutic effects of hemoperfusion in treating long-acting anticoagulant rodenticide poisoning Short running title: Treatment strategies for LAAR poisoning Dong Jianguang, Dr c # , Wu Jieyi, MD e# , Yin Bingling, MD f# , Peng Xiaobo, Dr d , Lu Xiaoxia, PhD d , Liu Zhongying, PhD d , Fan Haojun, PhD c , Liu Ziquan, PhD c , Qiu Zewu, PhD d , Wen Qiang, PhD b* , Pan Zhiguo, PhD a,f,g* , Lin Guodong, PhD a,b* Affiliations a The First Clinical Medical College, Southern Medical University, Guangzhou, 510515, China b Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, China c Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, 300072, China d Senior Department of Hematology, The Fifth Medical Center of PLA General Hospital, Beijing, 100071, China e Department of Anaesthesiology, General Hospital of Southern Theatre Command of PLA, Guangzhou, 510010, China f Department of Graduate School, Guangzhou University of Chinese Medicine, Guangzhou,510006, China g Department of Emergency Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou,510010, China # These authors contributed equally to this work. *Co-corresponding authors: Wen Qiang, Email: [email protected] Pan Zhiguo, Email: [email protected] Lin Guodong , Email: [email protected] The therapeutic effects of hemoperfusion in treating long-acting anticoagulant rodenticide poisoning Abstract Introduction: Second-generation anticoagulant rodenticides often cause severe bleeding, which can be life-threatening with limited effective treatment options. This study aimed to evaluate the therapeutic efficacy of hemoperfusion in patients with rodenticide poisoning. Methods: This study conducted a retrospective analysis of 148 patients diagnosed with rodenticide poisoning at the Fifth Medical Center of the Chinese PLA General Hospital between 2014 and 2021. The patients were divided into two groups based on whether they received blood purification treatment. The clinical characteristics, serum drug concentrations, duration of hospital stay, and duration of vitamin K1 (VK1) therapy were compared between the two groups using univariate and multivariate analyses. Subgroup analyses were also conducted to assess the effect of hemoperfusion in patients poisoned with brodifacoum and bromadiolone. Results: This retrospective study included 115 patients hospitalized for rodenticide poisoning. The patients were divided into a hemoperfusion group (24 patients) and a non-hemoperfusion group (91 patients). The hemoperfusion group demonstrated a faster reduction in serum drug concentration. The subgroup analysis revealed that hemoperfusion significantly reduced the duration of VK1 therapy in patients poisoned with brodifacoum (P=0.044). Conclusion: Hemoperfusion effectively reduced serum rodenticide concentrations in patients with poisoning. Moreover, the subgroup analysis suggested that hemoperfusion can reduce the duration of VK1 therapy in patients with brodifacoum poisoning. Keywords: long-acting anticoagulant rodenticide poisoning; hemoperfusion vitamin K1; maintenance treatment 1 Introduction Following the ban on first-generation rodenticides, second-generation anticoagulant rodenticides have emerged. These work primarily by disrupting the normal metabolism of vitamin K1 in the body, leading to vitamin K1 deficiency and, consequently, severe coagulation disorders. This can result in widespread bleeding and potentially life-threatening conditions in poisoned individuals 1. The main causes of poisoning include accidental ingestion, intentional poisoning, suicide, and numerous incidents of rodenticidal poisoning worldwide. Second-generation anticoagulant rodenticide poisoning is prevalent in China, particularly in economically underdeveloped rural areas 2. Bromadiolone and brodifacoum are the most commonly used second-generation anticoagulants. Once ingested, poisoning can cause multiple systemic bleeding episodes, including cerebral hemorrhage, and without prompt treatment, it can be life-threatening 3. The current treatment methods for anticoagulant rodenticide poisoning include vitamin K1 therapy, blood transfusions, and other supportive measures 4. Owing to the extremely long half-life of second-generation anticoagulant rodenticides, the elimination half-life can range from 243 to 1,656 h for brodifacoum 5. Some studies have reported that bromadiolone poisoning can last between 16 and 270 days 1. Effective treatments for severe cases of rodenticide poisoning, particularly for toxin removal, are lacking. Blood perfusion, a known detoxification method, has been shown to effectively remove various toxins, including heavy metals, pesticides, and drug overdoses 6. This study aimed to examine the role of hemoperfusion in the removal of rodenticide toxins from the body. 1 Introduction Methods Study design and population This study involved a retrospective analysis of 148 patients diagnosed with rodenticide poisoning at the Fifth Medical Center of the Chinese PLA General Hospital between 2014 and 2021. This study included all patients diagnosed with long-acting anticoagulant rodenticide (LAAR) poisoning based on blood poisoning test results and with hospital stays lasting longer than 24 h. Any patient with mixed poisoning, aged LAAR concentrations <5 μg/mL was excluded. The blood perfusion treatment protocol at our center involved continuous blood perfusion over 3 days, constituting one treatment course. Most patients underwent a single course of treatment, whereas a few required two courses of blood perfusion. This retrospective study adhered to the medical ethics standards and was approved by the appropriate ethics review board of the Fifth Medical Center of the Chinese PLA General Hospital (approval number: KY-2021-12-34-1). Since the study was retrospective, informed consent was waived from ethical review committee. To keep confidentiality of the collected data the personal identifiers were removed and unauthorized persons limited in their access to the data. The study was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies 7 . Statistical analyses Data analysis was performed using the Stata18.0. For data that followed a normal distribution, the results were expressed as mean ± standard deviation, and t-tests were used for comparisons between groups. For non-normally distributed data, continuous variables were reported as medians with interquartile ranges, and non-parametric tests were used for group comparisons. The chi-square test was used to analyze the contingency tables, whereas Fisher’s exact test was employed for contingency tables with small sample sizes. Logistic tests were performed to assess the prognosis and efficacy of blood perfusion in patients with rodenticide poisoning. Results were considered significant at p < 0.05. Results Baseline characteristics After applying the inclusion and exclusion criteria, 115 individuals were selected and divided into two groups: 24 in the hemoperfusion group and 91 in the non-hemoperfusion group (Figure 1). The univariate analysis revealed no significant differences in patient age or sex between the two groups (Table 1). However, the hemoperfusion group had a significantly longer hospital admission time than the non-hemoperfusion group (P=0.016). Moreover, there were no notable differences in clinical symptoms between the two groups. The blood drug concentration in the hemoperfusion group was significantly higher than that in the non-hemoperfusion group (520 (163–1174) ng/mL vs. 340 (145–1090) ng/mL) (P=0.000). Regarding the prognosis, the univariate analysis revealed no significant differences in hospitalization duration (P=0.939) or duration of VK1 therapy (P=0.282) between the two groups. Figure 1. Screening flowchart for the study. Table 1. Clinical characteristics of the patients. Demographic characteristics Male (%) 59（51.3） 13（54.2%） 46（50.4） 0.752 Age(year) 43（28-59） 43(28-52) 43(28-60) 0.621 Admission time, h 192（48-576） 1111.5（612.5-2632.5） 283（110-1020） 0.016 Blood concentration at admission, ng/mL 409(157-1174) 520(163-1174) 340(145-1090) 0.000 Coagulation at admission Normal coagulation, n(%) 21（18.3） 4（16.7） 17（18.7） 0.543 PT,s 27.7(15.9-164) 23.05(16.85-320) 30.2(15.7-137.3) 0.695 INR 2.55(1.49-16.63) 2.04(1.505-28) 2.93(1.44-13.75) 0.879 APTT,s 40.6（37-62.1） 40.25（37-80.75） 40.7（36-59.7） 0.804 Bleeding symptoms,n(%) 47（40.9） 9（37.5） 38（41.8） 0.676 hematuria 31（27.0） 6（25.0） 25（27.5） 0.516 epistaxis 21（18.3） 3（12.5） 18（19.8） 0.311 bleeding gums 16（13.9） 4（16.7） 12（13.2） 0.439 skin ecchymosis 12（10.4） 1（4.2） 11（12.1） 0.235 bloody stool 6（5.2） 3（12.5） 3（3.3） 0.104 joint bleeding 1（0.9） 0（0） 1（1.1） 0.791 abdominal pain 8（7.0） 3（12.5） 5（5.5） 0.217 waist aches 5（4.3） 1（4.2） 4（4.4） 0.721 thigh pain 3（2.6） 0（0） 3（3.3） 0.492 conjunctival hemorrhage 2（1.7） 0（0） 2（2.2） 0.625 Hospital stay, d 11.5(8-16) 14(9-15.5) 11(7-16) 0.190 Follow-up successful follow-ups，n n=89 n=15 n=74 Follow-up time, m 44(34-67) 43.5(38.5-60.5) 45(32-67) 0.939 total VK1 treatment time, d 14（8-34） 15（11-42） 14（8-34） 0.282 HP: Hemoperfusion; PT: prothrombin time; INR: international normalized ratio; APTT: activated partial thromboplastin time; VK1: vitamin K1 0.1 The role of blood perfusion in rodenticide poisoning 0.1.1 Multivariate analysis results The multivariate analysis, which included factors such as age, sex, admission time, and toxin concentration at admission, revealed no significant effect of hemoperfusion treatment on the hospital stay (P=0.475) or total VK1 treatment time (P=0.656) (Table 2 and Figure 2). Further subgroup analysis revealed no significant difference in hospital stay (P=0.390) between patients with bromadiolone poisoning and those who underwent hemoperfusion. However, the hemoperfusion therapy significantly reduced the duration of VK1 therapy in patients with bromadiolone poisoning (P=0.044). Table 2. Association between hemoperfusion (HP) use and the duration of hospital stay/duration of VK1 therapy using a logistic approach. 0.1 The role of blood perfusion in rodenticide poisoning Hospital stay All LAAR poisoning group 1.021 (0.964-1.082) 0.475 BDL poisoning group 1.045 (0.945-1.155) 0.390 Total VK1 treatment time All LAAR poisoning group 1.002 (0.993-1.011) 0.656 BDL poisoning group 0.875 (0.769-0.996) 0.044 HP: Hemoperfusion; VK1: Vitamin K1; LAAR: Long-acting anticoagulant rodenticide; BDL: Bromadiolone; Figure 2. Forest plot of hemoperfusion (HP) treatment for LAAR poisoning. Trends in blood rodenticide concentrations As illustrated in Figure 3, both the hemoperfusion and non-hemoperfusion groups exhibited a decreasing trend in blood rodenticide concentrations throughout hospitalization. However, the hemoperfusion group demonstrated a faster reduction in blood drug concentrations than the non-hemoperfusion group. Figure 3. The concentration of the drug in the blood of patients in the hemoperfusion and non-hemoperfusion groups showed a decreasing trend with the duration of hospitalization. Effect of hemoperfusion on blood rodenticide concentrations During treatment, the blood rodenticide concentrations of nine patients with bromadiolone poisoning who underwent hemoperfusion were measured before and after each session (Figure 4). Our research serves as a preliminary exploration in this area. In the 2012 article by the EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup on guideline methodology, methods for assessing the effectiveness of blood purification in toxin clearance were discussed. As shown the methods in the study, given that the volume of distribution (Vd) for second-generation anticoagulant rodenticides exceeds 5 L/kg, primary criteria should be favored. As the blood toxin concentration can reflect overall body burden (A=Vd*C), the difference in blood concentration before and after hemoperfusion can indicate the amount of toxin cleared. The clearance rate of bromadiolone varied among the patients and ranged from a minimum of 3.1% to a maximum of 42.7%. Eight of the nine patients showed an increasing clearance trend with daily hemoperfusion. Additionally, the toxin concentration in one patient with brodifacoum poisoning was monitored before and after each hemoperfusion session, showing a clearance rate of 10.8% to 18.2% per session (Figure 4). Figure 4. The test results of blood toxin concentrations of nine patients with bromadiolone poisoning and one with brodifacoum poisoning before and after multiple hemoperfusion sessions. Discussion In our study, the multivariate analysis revealed that blood perfusion reduced the duration of vitamin K1 treatment in patients with bromadiolone poisoning. A comparison of the overall blood toxin concentrations between the blood perfusion and non-perfusion groups revealed a faster decrease in the perfusion group. Moreover, the concentration of toxins in the blood consistently decreased before and after each blood perfusion session. Second-generation anticoagulant rodenticides primarily include bromadiolone and brodifacoum. These rodenticides are characterized by high lipid solubility and long half-lives 8 . Research indicates that brodifacoum is significantly more toxic than bromadiolone, with higher lipid solubility and a longer half-life 1 . Vitamin K1 is an antidote for second-generation rodenticides; however, standardized protocols for vitamin K1 treatment are lacking. Based on our center’s experience, we have proposed several treatment strategies 9 . However, challenges remain in vitamin K1 treatment, particularly in patients with high toxin concentrations where large doses are required during the acute phase 10 . Previous studies have reported a wide range of doses that often exceed the recommended levels. Our center has found that large doses of vitamin K1 are frequently administered early in treatment, surpassing the usage guidelines. This has raised significant safety concerns. Patients in the acute phase of severe rodenticide poisoning often experience severe coagulation dysfunction 10 . Although blood transfusion combined with vitamin K1 is commonly used, this approach does not effectively eliminate toxins from the body 4 . Excessive toxins pose a substantial risk of worsening the patient’s condition, and timely removal of these toxins is crucial 12–13 . Currently, there are no effective methods for the rapid clearance of rodenticide toxins. Although blood perfusion has been shown to clear various toxic substances, its efficacy against rodenticide poisoning remains unclear 6,14 . Theoretically, blood perfusion may not be ideal for clearing toxins with high lipid solubility and large apparent distribution volumes 15 . Studies have shown that difenacoum has a significantly larger apparent volume of distribution (10.4 ± 1.4 L/kg) compared to warfarin (0.65 ± 0.1 L/kg). Although no distribution volume data are available for bromadiolone or brodifacoum, their longer half-lives suggest that their apparent volume of distribution exceeds that of warfarin 16 . Nevertheless, blood perfusion may still be an effective option for patients with known high concentrations of rodenticides in their blood. This study aimed to investigate the role of blood perfusion in patients with rodenticidal poisoning based on this premise. Our research yielded several key findings: 1) In terms of short-term effects, blood perfusion significantly reduced the blood toxin concentrations, with a greater rate of decline in the perfusion group than in the non-perfusion group. 2) For the overall poisoned population (including both bromadiolone and brodifacoum cases), blood perfusion did not reduce the total duration of vitamin K1 treatment. However, it shortened the total duration of vitamin K1 therapy in patients with bromadiolone poisoning. We offer the following explanation for our findings: our study demonstrated the efficacy of blood perfusion in clearing rodenticide toxins from three perspectives—direct evidence (the immediate drop in blood toxin concentration before and after perfusion), indirect evidence (the decreasing trend in blood toxin levels during hospitalization in patients that underwent perfusion), and multivariate analysis, which revealed that blood perfusion reduced the total duration of vitamin K1 treatment in cases of bromadiolone poisoning. Therefore, blood perfusion can help eliminate toxins from the blood. The subgroup analysis suggested that blood perfusion may have a better clearance effect on bromadiolone than on brodifacoum, leading to a reduced total amount of vitamin K1. Based on these findings, we speculate that bromadiolone may have lower lipid solubility and a smaller apparent volume of distribution than brodifacoum, resulting in higher blood toxin concentrations after poisoning. Consequently, blood perfusion may be more effective in clearing toxins from the blood in cases of bromadiolone poisoning. Conclusion Hemoperfusion demonstrated a toxin-clearing effect by reducing the blood rodenticide concentrations. However, this did not significantly shorten the overall duration of vitamin K1 treatment. Still, the subgroup analyses suggested that hemoperfusion may help reduce the duration of vitamin K1 treatment, especially in cases of bromadiolone poisoning. Funding information This study was supported by the National Natural Science Foundation of China (No. 82202432) and the Guangzhou Science and Technology Plan Project (No. 2023A04J2059, 2024A03J0242) Disclosure statement The authors report there are no competing interests to declare. Data availability Data is provided within the manuscript files. References 1. King N, Tran MH. 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Tveden-Nyborg P, Bergmann TK, Jessen N, Simonsen U, Lykkesfeldt J. BCPT 2023 policy for experimental and clinical studies. Basic Clin Pharmacol Toxicol. 2023;133:391-396 8. Bruno GR, Howland MA, McMeeking A, et al. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med. 2000;36(3):262-267. doi:10.1067/mem.2000.108317 9. Guodong L, Jieyi W, Xiaobo P, et al. Retrospective analysis of clinical characteristics of and treatment strategies for patients with long-acting anticoagulant rodenticide poisoning. Basic Clin Pharmacol Toxicol. 2022;131(1):74-82. doi:10.1111/bcpt.13734 10. Tsutaoka BT, Miller M, Fung SM, Patel MM, Olson KR. Superwarfarin and glass ingestion with prolonged coagulopathy requiring high-dose vitamin K1 therapy. Pharmacotherapy. 2003;23(9):1186-1189. doi:10.1592/phco.23.10.1186.32755 11. Xiang L, Min Z, Alan Z, et al. Retrospective study of twenty-four patients with prolonged coagulopathy due to long-acting anti-vitamin K rodenticide poisoning. Am J Med Sci. 2014;347(4):299-304. doi:10.1097/MAJ.0b013e318291cb7d 12. Chinese Society Of Toxicology Poisoning And Treatment Of Specialized C, Poisoning Group Of Emergency Medicine Branch Of Chinese Medical A. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2021;33(4):385-392. doi:10.3760/cma.j.cn121430-20210305-00338 13. Ke J, Wei Y, Chen B. Application of Hemoperfusion in the Treatment of Acute Poisoning. Blood Purif. 2024;53(1):49-60. doi:10.1159/000532050 14. Ferrari F, Manera M, D’Auria L, et al. Hemoperfusion in Poisoning and Drug Overdose. Contrib Nephrol. 2023;200:218-241. doi:10.1159/000526730 15. Lavergne V, Nolin TD, Hoffman RS, et al. The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology. Clin Toxicol (Phila). 2012;50(5):403-413. doi:10.3109/15563650.2012.683436 16. Breckenridge AM, Cholerton S, Hart JA, et al. A study of the relationship between the pharmacokinetics and the pharmacodynamics of the 4-hydroxycoumarin anticoagulants warfarin, difenacoum and brodifacoum in the rabbit. Br J Pharmacol. 1985;84(1):81-91. Information & Authors Information Version history V1 Version 1 01 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords hemoperfusion vitamin k1 long-acting anticoagulant rodenticide poisoning maintenance treatment Authors Affiliations Dong Jianguang Tianjin University View all articles by this author Wu Jieyi People's Liberation Army General Hospital of Southern Theatre Command View all articles by this author Yin Bingling 0009-0008-4832-3817 Guangzhou University of Chinese Medicine View all articles by this author Peng Xiaobo 5th Medical Center of Chinese PLA General Hospital View all articles by this author Lu Xiaoxia 5th Medical Center of Chinese PLA General Hospital View all articles by this author Liu Zhongying 5th Medical Center of Chinese PLA General Hospital View all articles by this author Fan Haojun Tianjin University View all articles by this author Liu Ziquan Tianjin University View all articles by this author Qiu Zewu 5th Medical Center of Chinese PLA General Hospital View all articles by this author Wen Qiang People's Liberation Army General Hospital of Southern Theatre Command View all articles by this author Pan Zhiguo People's Liberation Army General Hospital of Southern Theatre Command View all articles by this author Lin Guodong 0000-0001-5978-6288 [email protected] People's Liberation Army General Hospital of Southern Theatre Command View all articles by this author Metrics & Citations Metrics Article Usage 227 views 79 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Dong Jianguang, Wu Jieyi, Yin Bingling, et al. 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