Extracorporeal blood purification and associated extracorporeal therapies (ECT) are used for management of an array of pathologies. Therapeutic plasma exchange (TPE) is an ECT technique that can be used for severe intoxication and immune-mediated disease.
Background
TPE involves circulating a patient’s blood through an external device that separates the plasma layer from other blood components via a membrane- or centrifugal-based system. The plasma is then discarded, and cellular components are recombined with a replacement fluid (eg, donor plasma, albumin, synthetic colloid, crystalloid) and returned to the patient. The ideal toxicant that can be removed using TPE is moderate in size, is highly protein bound, and has a small volume of distribution.
TPE sessions require several critical steps, typically starting with attaining vascular access via placement of a dialysis catheter in the jugular vein that terminates at the level of the right atrium. Regional (eg, citrate) or systemic (eg, unfractionated heparin) anticoagulation is then used to prevent clot formation in the circuit. A TPE session lasts 2 to 4 hours, with the patient awake or lightly sedated and continuously monitored, to allow processing of 1.6 to 2 times the plasma volume, which removes >75% of the substance of interest.1 For example, an ≈44-lb (20-kg) dog receiving TPE for NSAID toxicosis with a goal of 1.6 to 2 times plasma volume exchanged should receive 800 mL to 1.6 L (based on 90 mL/kg blood volume) of replacement solution in a desired percentage of plasma, colloid, or crystalloid. The number of plasma volumes exchanged is based on an estimated clearance curve for substances within the intravascular compartment.1 For substances with a large volume of distribution, more plasma volumes would need to be exchanged to allow for higher clearance as the substance of interest equilibrates across the compartments during removal. The replacement fluid choice depends on pretreatment biochemical values, the patient’s hemodynamic status during the session, patient size, cost, and plasma availability in the clinic. Cost can be high based on the volume and type of replacement solution used. Usually, only 1 or 2 (rare) TPE sessions are needed for severe NSAID toxicosis.
Although guidelines for use of ECT, including TPE, in veterinary medicine continue to emerge, a growing body of evidence supports this option. In general, TPE has a good safety profile, with a reported complication rate of 34% (22/64) for all TPE sessions in a retrospective study.2 Most complications were mild (20/22) and included vomiting, diarrhea, sneezing, urticaria, laryngeal edema, chemosis, system clotting, and technical problems. Some complications are secondary to a type I hypersensitivity reaction as a result of plasma administration. Hypocalcemia is an additional potentially life-threatening complication reported in association with large volumes of plasma administered rapidly and regional anticoagulation using citrate.3 Hypocalcemia is mitigated by supplementation with parenteral calcium during treatment and frequent intermittent monitoring of ionized calcium concentration.
Multiple factors should be considered before selecting an ECT for intoxication, including toxicokinetic suitability (ie, volume of distribution, molecular weight, protein binding), time sensitivity (typically <4-6 hours following exposure), lack of antidote or other therapy, and favorable risk:benefit ratio (patient safety and benefit).4,5 Early consultation with a specialist is recommended in standard case management in which TPE or other ECTs may be beneficial. More research to evaluate the specific indications and outcomes of TPE in veterinary medicine is needed.
Following are the top 3 indications for TPE in veterinary patients according to the authors.
1. NSAID Toxicosis
NSAIDs inhibit cyclooxygenase and its isoenzymes with varying degrees of selectivity. These enzymes convert arachidonic acid into prostaglandins, which are important for regulating inflammation, GI mucosal health, and maintaining glomerular filtration rate.
NSAID overdose can result in GI adverse effects, acute kidney injury, and CNS dysfunction, depending on the dose. There is no specific antidote, and treatment is largely supportive. NSAIDs exhibit high protein binding, making TPE a treatment option. Several reports have demonstrated positive outcomes in dogs and cats following TPE treatment for meloxicam, naproxen, carprofen, and ibuprofen overdose.6-9 In one case report, pharmacokinetic modeling of TPE for meloxicam overdose in a dog showed a decreased elimination half-life and increased clearance compared to standard pharmacokinetic parameters.6 Additional studies on TPE for carprofen overdose in dogs have documented reduction in plasma carprofen concentrations using high-performance liquid chromatography.7,8 No organ damage was documented in these dogs following toxic NSAID exposure. Outcomes in >400 dogs with NSAID toxicosis treated with medical management alone with or without the addition of TPE has been described; a lower incidence of acute kidney injury was found in patients given TPE that were exposed to either a renal or CNS toxic dose of an NSAID.9
2. Immune-Mediated Hemolytic Anemia
Immune-mediated hemolytic anemia (IMHA) is an immune-mediated disease that results in production of anti-RBC antibodies. The innate immune system targets these tagged RBCs for destruction, leading to severe anemia, autoagglutination, spherocytosis, hyperbilirubinemia, thrombocytopenia, and activation of the coagulation system. TPE can be used to remove circulating immune complexes, complement substrates, and immunoglobulins (eg, immunoglobulin M) that can bind to and label RBCs for destruction.10 Studies have demonstrated a 37% to 78% reduction in immunoglobulin G and M levels with TPE use in IMHA patients.10
Hyperbilirubinemia may also result from IMHA and can lead to acute bilirubin encephalopathy. Studies have reported positive outcomes and significant reductions in bilirubin following daily treatment with TPE in patients with severe IMHA.2,10 Immunosuppressants can take up to 1 week or longer to effectively halt RBC destruction. TPE could be considered in IMHA cases with rapid hemolysis in the setting of transfusion, in cases complicated by severe hyperbilirubinemia resulting in neurologic signs, and in patients requiring several blood transfusions due to ongoing severe hemolysis. TPE is useful during the first week of immunosuppressant therapy, before these agents reach maximum efficacy. The number of treatments depends on the severity of hyperbilirubinemia and hemolysis, as well as individual patient response to initial TPE sessions, but typically is a combination of multiple sessions over several days (eg, 3 sessions at a minimum of 24 hours apart) to achieve effective plasma clearance.
Another commonly diagnosed hematologic immune-mediated disease in dogs is immune-mediated thrombocytopenia (ITP). One case series described 4 dogs with ITP that were presented with a history of severe bleeding and underwent TPE; 3 dogs had increased platelet counts and resolution of bleeding following TPE.11 More research is needed to determine specific protocols for TPE, ideal timing for intervention, and benefits of treating other immune-mediated diseases in veterinary medicine.
3. Acquired Myasthenia Gravis
Myasthenia gravis (MG), in which a reduced number of functioning acetylcholine receptors exist on the postsynaptic cleft of the neuromuscular junction, can be congenital or acquired. Acquired MG is an immune-mediated condition in which antibodies are produced against the acetylcholine receptor on the postsynaptic side of the neuromuscular junction. Clinical presentation can vary depending on whether the disease manifests as focal, generalized, or fulminant. Human literature supports TPE as an effective treatment option for acquired MG and reports a higher response rate compared to treatment with IV immunoglobulin.12
In a case series, 3 dogs were given TPE after failing medical management. TPE was chosen for these patients because clinical signs persisted after medical management, clinical signs were stabilized prior to general anesthesia and thymectomy, and myasthenic crisis led to respiratory failure secondary to aspiration pneumonia. Rapid clinical improvement (ie, improvements in muscle weakness, ptyalism, paraparesis, dysphagia) was noted in 2 dogs, and 2 dogs had decreased acetylcholine antibody titers.13 More research is needed to determine the specific indications and clinical scenarios for TPE use in dogs with MG.
Conclusion
TPE can be resource intensive, but its ability to decrease morbidity and mortality in patients with severe intoxication or severe life-threatening immune-mediated disease may provide a treatment option in cases with otherwise limited alternatives. Understanding the logistics of TPE implementation, including specialized equipment and expertise, is important when providing treatment options to pet owners.