An Update on Extracorporeal Therapies for Exogenous and Endogenous Toxins

Shawn Kearns, DVM, DACVIM
angell.org/internalmedicine
internalmedicine@angell.org
617-541-5186

x

x

x

The canine patient (not pictured) received lipids prior to treatment, resulting in the milky fluid on the effluent/collection bag.

Extracorporeal therapies (ECT) in veterinary medicine are an advanced modality for the treatment of acute kidney injury (hemodialysis; HD), autoimmune diseases (therapeutic plasma exchange; TPE), and toxicities. Since 2015, the number of toxicity cases treated with advanced modalities has significantly increased, likely due to increased access to equipment, increased training, and drawing on experiences from human medicine. In human medicine, the use of ECTs has also increased over the years from ~0.1% use in all poisoning¹ to ~0.45%² use. Many substances have a large safety margin and are safe when exposed in isolation. There may be medical means for treatment, but ECT may be considered when this is not the case.

Deciding whether to consider hemodialysis, TPE, hemoperfusion (HP), or a combination of therapies for toxicity should be based on several factors. Keeping in mind the metabolism of a substance may be altered depending on the quantity the patient ingested, the first question to ask is whether using advanced therapies will lead to a higher or faster extraction rate than what the body may metabolize. If allowing the substance to be metabolized endogenously could be lethal or lead to significant or irreversible organ damage, ECT should be a consideration. Second, determine whether the substance could cause a progressive deterioration in clinical status or depression of midbrain function leading to hypoventilation, hypothermia, and hypotension or if the patient is already demonstrating neurologic decline. If the patient has a pre-existing condition that may impair drug or substance excretion, ECT may be an added tool along with other medical therapies. In veterinary medicine, a challenge in determining the benefit of ECT includes often not knowing the exact timing of exposure and/or the exact dose ingested, and treatment recommendations are often based on the suspected maximal dose ingested or severity of signs (for example- neurological) at presentation.

Not all substances are amenable to clearance by each ECT modality. The choice of clearance therapy mode depends on the molecule’s size, the degree of protein binding, and the volume of distribution. Typically, only low molecular weight substances (10,000 daltons) that are less than 80% protein bound with a low volume of distribution (< 2L/kg) can be cleared with diffusion-based HD. Machines that are capable of convection-based HD can clear slightly larger molecules, but their capacity is still low.  Ethylene glycol, ivermectin, metaldehyde, phenobarbital, and baclofen ingestion have been successfully treated with hemodialysis in the veterinary literature.^{3, 4, 5, 6}

The canine patient received TPE for ingestion of an NSAID overdose.

Although more studies are needed to determine how large of a molecule can be cleared with hemoperfusion (charcoal or the newer carbon-based therapies), it is thought to be high.¹ Hemoperfusion filters can be used in tandem on hemodialysis platforms or as a stand-alone therapy using a blood pump. In addition, use with other therapies, such as intravenous lipids, may aid in the capture of some molecules. The majority of hemoperfusion reports are associated with non-steroidal anti-inflammatory ingestion (carprofen, ibuprofen, meloxicam).^{7, 8, 9} After ingestion of a massive dose (550mg/kg) of extended-release 5-hydroxytryptophan (5-HTP) a dog was treated with a combination of hemoperfusion and hemodiafiltration. Treatment was successful, and serial plasma samples indicated that the extraction of 5-HTP was 93.6% to 98.9%.¹⁰ methotrexate treatment with charcoal HP in combination with HD has also been reported.¹¹ Manual HP may be considered to reduce the blood circuit volume for very small patients or when other specialty equipment is unavailable. This technique was used successfully in a feline patient after an accidental overdose of injectable meloxicam (0.48mg/kg SQ), and the meloxicam blood level was reduced by ~44% with a 60-minute treatment.⁹

Therapeutic plasma exchange is recommended for larger molecules that are highly protein-bound and is the most common therapy reported for ingestion of non-steroidal anti-inflammatory drug (NSAID) overdoses.^12-20 Reduction in plasma levels after one treatment, typically ~1.5 plasma volumes, are reported to be 50% to 85% for NSAIDs. Although TPE +/- additional therapies (intravenous lipids; ILE) may not completely eliminate the risk of acute kidney injury or gastrointestinal disturbances with NSAID overdoses, it may reduce the magnitude in instances where the total dose ingested is extremely high or the half-life is longer, such as with naproxen. Other reports of TPE use include treatment of bifenthrin (pyrethroid insecticide) ingestion²¹ and an inadvertent overdose of intravenous lipids.²² As with hemoperfusion, manual therapeutic plasma exchange has also been reported.^{20, 22}

Rarely, endogenous toxins may pose significant enough health risks to warrant removal via extracorporeal therapies. High serum bilirubin levels have been reported in humans and animals to cause neurologic signs. In addition, renal tubular injury may also occur from high bilirubin levels. TPE may be considered in cases with severe hyperbilirubinemia secondary to autoimmune hemolytic anemia leading to kernicterus, which has been reported in dogs.^{23, 24} TPE has also been reported for treating one dog with hepatic encephalopathy prior to shunt correction. In this case, ammonia levels decreased by ~50%, and the patient improved clinically.²⁵ An 8-year-old British shorthair that developed neurologic signs and MRI findings consistent with post-attenuation neurologic signs (PANS) was also treated with TPE after failing medical management, including general anesthesia and mechanical ventilation. Seizure activity stopped immediately after the TPE treatment, and the patient showed progressive improvement.²⁶

Although specific guidelines for when to intervene with more advanced therapies should be developed, ECT is a growing field for toxicities.  In most cases, the key to successful treatment is an early referral. However, initial decontamination (induction of emesis, activated charcoal), as dictated by a poison control center or patient stability, should be done before referral. Candidate cases are best treated within 24 hours or less of exposure, sooner if possible. While it is hard to conclude the prognosis for individual reports on toxin exposures, the prognosis with the treatment of NSAID overdoses is excellent.^{17, 18} We can offer all three therapy platforms for our veterinary patients at Angell Animal Medical Center.

x

References

1. Ghannoum M, Roberts DM, Hoffman RS et al. Seminars in dialysis. Vol 27 (4) 2014 P 362-370
2. King JD, Kern MH, Jaar BG. Extracorporeal removal of poisons and toxins. Clin J Am Soc Nephrol. 2019 Aug 22; 14 (9): 1408-1415
3. Londono LA, Buckley GJ, Bolfer L et al. Clearance of plasma ivermectin with single pass lipid dialysis in 2 dogs. J Vet Emerg Crit Care2017 Mar; 27 (2): 232-237.
4. Teichmann-Knorm S, Doerfelt S, Doerfelt R. Retrospective evaluation of the use of hemodialysis in dogs with suspected metaldehyde poisoning (2012-2017): 11 cases. J Vet Emerg Crit Care. March 2020; 30 (2): 194-201.
5. Basile JK and Vigani A. Treatment of phenobarbital intoxication using hemodialysis in two dogs. J Vet Emerg Crit Care. March 2020; 30 (2): 221-225.
6. Hoffman L, Londono LA, Martinz J. Management of severe baclofen toxicosis using hemodialysis in conjunction with mechanical ventilation in a cat with chronic kidney disease. J Feline Med Surg. 2021. Open Rep Jul-Dec;7(2):20551169211033770
7. Fick ME, Messenger KM, Vigani A. Efficacy of a single session in-series hemoperfusion and hemodialysis in the management of carprofen overdose in two dogs. J Vet Emerg Crit Care. March 2020; 30 (2): 226-231.
8. Tauk BS and Foster JD. Treatment of ibuprofen toxicity with serial charcoal hemoperfusion and hemodialysis in a dog. J Vet Emerg Crit Care. Nov 2016; 26 (6): 787-792.
9. Haire LE, Vitalo AD, Goncalves RP et al. Case Report: Manual carbon hemoperfusion for the treatment of meloxicam toxicity in a cat and suspected ibuprofen toxicity in a dog. Frontiers. Sept 2024. DOI 10.3389/fvets.2024.1395967
10. Her J, Gordon D, Riggs A. Successful treatment of a severe 5-hydroxytrytophan intoxication using carbon hemoperfusion, hemodiafiltration, and mechanical ventilation in a dog. J Vet Emerg Crit Care. 2024 Mar-Apr; 34 (2): 186-192.
11. Pardo M, Lanaux T, Davy R. Use of charcoal hemoperfusion and hemodialysis in the treatment of methotrexate toxicosis in a dog. J Vet Emerg Crit Care. May 2018; 28 (3): 269-273.
12. Rosenthal MG, Labato MA. Use of therapeutic plasma exchange to treat nonsteroidal anti-inflammatory drug overdose in dogs. J Vet Intern Med2019 Mar-Apr; 33 (2): 596-602
13. Kicera-Temple K, Londono L, Lanaux TM et al. Treatment of massive naproxen overdose using therapeutic plasma exchange in a dog. Clin Case Rep. August 2019; 7 (8): 1529-1533
14. Walton S, Ryan KA, Davis JL et al.Treatment of ibuprofen intoxication in a dog via therapeutic plasma exchange. J Vet Emerg Crit Care. July 2017; 27 (4): 451-457.
15. Walton S, Ryan KA, Davis JL et al. Treatment of meloxicam overdose in a dog via therapeutic plasma exchange. J Vet Emerg Crit Care. July 2017; 27 (4): 444-450.
16. Kjaergaard AB, Davis JL, Acierno MJ. Treatment of carprofen overdose with therapeutic plasma exchange in a dog. J Vet Emerg Crit Care. July 2018; 28 (4): 356-360.
17. Chalifoux NV, Butty EM, Mauro KD et al. Outcomes of 434 dogs with non-steroidal anti-inflammatory drug toxicosis treated with fluid therapy, lipid emulsion, or therapeutic plasma exchange. J Vet Intern Med. 2023; 37: 161-172
18. Groover J, Londono LA, Tapia-Ruano K et al. Extracorporeal blood purification in acutely intoxicated veterinary patients: a multicenter retrospective study (2011-2018): 54 cases. J Vet Emerg Crit Care. 2022 January; 32 (1): 34-41.
19. Cambournac M, Moumadah Y, Berny P et al. Treatment of flurbiprofen overdose with therapeutic plasma exchange in a dog. Vet Rec Case Rep. 2023 March; 11 (1): e539.
20. Buseman M, Blong AE, Walton RA. Successful management of severe carprofen toxicity with manual therapeutic plasma exchange in a dog. J Vet Emerg Crit Care. 2022 September; 32 (5): 675-679.
21. Fitzgerald AH, Davies RK, Zhang Y et al. Successful treatment of bifenthrin toxicosis using therapeutic plasma exchange.  J Vet Emerg Crit Care. 2024 May-Jun; 34 (3): 291-295.
22. Epstein SE, Hopper K, Farrell KS. Manual plasma exchange to treat an accidental overdose of intravenous lipid emulsion in a dog with baclofen toxicosis. JAVMA. Mar 2022; 260 (6): 650-655.
23. Heffner GG, Cavanagh A, Nolan B. Successful management of acute bilirubin encephalopathy in a dog with immune medicated hemolytic anemia. J Vet Emerg Crit Care. Sept 2019; 29 (5): 549-557.
24. Tovar T, Deitschel S, Guenther C. The use of therapeutic plasma exchange to reduce serum bilirubin in a dog with kernicterus. J Vet Emerg Crit Care. July 2017; 27 (4): 458-464.
25. Culler CA, Reinhardt A, Vigani A. Successful management of clinical signs associated with hepatic encephalopathy with manual therapeutic plasma exchange. J Vet Emerg Crit Care2020 May 30 (3): 312-317
26. Niemann L, Beckmann K, Iannucci C et al. Diagnosis of post-attenuation neurologic signs syndrome in a cat with refractory status epilepticus and clinical response to therapeutic plasma exchange. J Feline Med Surg. Open Rep. 2022 Jul-Dec;8(2):20551169221121919.