PlasmapheresisDrug Information QuestionPS-3 Advanced Practice Experience Rotation FTodd S. Reese, PharmD Candidate, MWU-CPGLiterature search current as of: 05/12/07

Question: Compare and contrast key components of plasmapheresis to hemodialysis. Focus on drug characteristics that determine ease of drug removal from the plasma. Provide a list of common medications that may require additional monitoring or supplemental dosing during plasmapheresis.

Answer:

Plasmapheresis, also known as “apheresis” and “therapeutic plasma exchange” (TPE) is becoming popular for treatment of infectious and immunologic diseases, metabolic disorders, and inherited illnesses. This procedure separates plasma from the cellular components of blood. Once the plasma is separated, solutes in the blood (including drugs) can be filtered out. Since plasmapheresis can affect the pharmacokinetics of various medications, it is paramount that pharmacists understand the dynamics in order to provide optimal healthcare to patients.1

Hemodialysis is a method used primarily for removing waste products such as urea, potassium, and free water from the blood in acute and chronic renal failure. The advantage of TPE, in comparison, is that it is designed for the extracorporeal removal of large molecular weight substances such as pathogenic antibodies, cryoglobulins, myeloma light chains, immune complexes, endotoxins, and cholesterol-containing lipoproteins.1 By removing these substances, TPE can reduce and/or eliminate further damage, thus, reversing the pathologic process. TPE can remove varying size toxins, including protein-bound and lipid-bound toxins, as well as red blood cells destroyed by toxin-induced hemolysis. See Clinical Pearl 1 for drug characteristics that determine the need for TPE.

Figure 1 shows the schematic of the plasmapheresis procedure. A comparison between plasmapheresis and hemodialysis is provided in Table 1.

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Clinical Pearl 1Drug Characteristics That Determine the Ease of Removal in Therapeutic Plasma Exchange3

The patient must have at least one of the following conditions for TPE to be a rational therapeutic choice: • The substance to be removed should be sufficiently large with a molecular weight greater than 15,000 Daltons. Otherwise, it could be removed by less expensive filtering such as hemofiltration or high-flux hemodialysis.

• The substance to be removed must have a long half-life, such that extracorporeal removal is more rapid than the body’s normal clearance mechanisms.

• The substance to be removed should be acutely toxic and/or resistant to typical therapy; such that TPE’s rapid elimination from the extracellular fluid is indicated.

Since large molecular weight compounds equilibrate slower than smaller ones over the vascular space and the interstitium, TPE removal of these compounds is generally simplified to first order kinetics. Therefore, one plasma volume exchange is estimated to lower macromolecule levels by 60%.2 The following formula may be used to estimate the plasma volume: Volume (Liters)  =   0.07  x  wt (kg)  x  (1  -  hematocrit).2

This equation can help predict the time needed for a volume exchange. Current cell separators can complete one volume exchange in approximately 1.5 to 2 hours. Multiple exchanges, therefore, can increase procedure time, fatigue the patient, and increase cost. In most exchanges, a 1 to 1.5 plasma exchange is required.2 In drug-induced illnesses, however, many plasma exchanges may be necessary. In amiodarone-associated alveolitis, for example, five plasma exchanges may be required.1

To replace the volume of fluid lost through TPE, replacement fluids such as fresh-frozen plasma, 5% albumin, or other plasma type derivatives (such as cryosupernatant) and crystalloids are given to the patient. In general, the replacement fluid has an impact on the efficacy of the procedure, the ability of proteins to pass through cell walls, coagulation, and has various adverse effects. Albumin (in a 50:50 mixture with 0.9% saline) is a better choice than plasma as it reduces the risk of hypersensitivity reactions and limits the transmission of viral infections.3 More importantly, the composition of the fluid replacement must be tailored to the needs of the patient. Patients at risk of bleeding (liver disease or disseminated intravascular coagulation) or those who will require numerous exchanges, should only receive fresh-frozen plasma (FFP).3

The most common and major side effect of plasmapheresis is bleeding from a central venous catheter.4 Management of the problem includes considering using venipuncture instead of a permanent catheter, especially if the central catheter is for the explicit use for TPE only. Other side effects of TPE include allergic type I hypersensitivity4,5, hypotension, dyspnea, citrate-induced hypocalcemia (citrate in the anticoagulant can bind with the calcium), citrate-induced metabolic alkalosis, coagulation abnormalities, and infection.5 Anaphylactic reactions to FFP represents a serious complication of TPE, reported in up to 21% of patients.5 Healthcare workers should note that a reaction is often shown by fever, rigors, rash, wheezing, and hypotension. The risk of a reaction may be reduced by pretreatment with diphenhydramine, corticosteroids, and/or epinephrine.5

TPE has excellent use for acute drug overdoses. A partial list of drugs for which TPE was used and studied for acute overdoses appears at the right with the corresponding levels of the drug before and after.1

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Drug TPE exchanges

Levels before TPE

Levels after TPE

Phenytoin 3 98 mg/L 38 mg/LParathion 3 0.7 mg/L 0.01 mg/LCarbamazepine 3 42.8 mg/L 15 mg/LTheophylline 1 100 mg/L 64 mg/LDigoxin 2 14.1 ng/mL 6.4 ng/mLVincristine 1 7.1 ng/mL 5.5 ng/mLCisplatin 3 2900 ng/mL 200 ng/mL

TPE can be used for the treatment of infectious and immunologic disease, metabolic disorders, and inherited illness. Since many people with these conditions are also on various medications, it is important to note that plasmapheresis can and will eliminate other drugs in the bloodstream which are beneficial to the patient. Some drugs will require supplemental doses, while additional doses may not be needed for others. Clinical Pearl 2 summarizes a few drugs which have been studied and whether supplementation is necessary:1

In conclusion, plasmapheresis is an excellent tool available for a variety of situations in which the traditional methods of filtering are not appropriate. It is especially useful for some specific diseases such as thrombotic thrombocytopenia purpura (TTP), myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, Waldenstroms macroglobulinemia, and Guillain-Barre syndrome.2 More studies are needed to see how common drugs react to plasmapheresis and whether supplemental dosing is necessary.

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Clinical Pearl 2

Drug Supplementation Necessary?

Comment

Prednisone No

Digoxin No

ASA Yes

Propanolol No Pt. may experience rebound

Cyclosporine No

Ceftriaxone No If TPE within 12 hours

Ceftazidime No

Tobramycin Unclear Further studies needed

Valproic acid No

Phenobarbital No

Phenytoin Results vary by number of exchanges

Must monitor unbound Phenytoin to adjust dose

Figure 1 – Plasmapheresis3

1 Kale-Pradham, Pramodini B. A Review of the Effects of Plasmapheresis on Drug Clearance. Pharmacotherapy 1997;17(4):684-695.

2 Fridey, Joy L. and Andre A Kaplan. Indications for Therapeutic Plasma Exchange. Last updated July 24, 2003. Accessed online via www.uptodate.com, 2007 May 12.

3 Madore, François and Hugh R. Brady. Plasmapheresis in Renal Diseases, Chapter 14. Accessed online via www.elsevier-international.com/e-books/pdf/567.pdf.

4 Von Baeyer, Hans. Plasmapheresis in Immune Hematology: Review of Clinical Outcome Data with Respect to Evidence-Based Medicine and Clinical Experience. Therapeutic Apheresis and Dialysis 7(1):127–140, 1 February 2003.

5 Fridey, Joy L. and Andre A Kaplan. Complications of Therapeutic Plasma Exchange. Last updated July 24, 2003. Accessed online via www.uptodate.com, 2007 May 12.

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Table 1 – Plasmapheresis/Hemodialysis Comparison2,5,6,7

Plasmapheresis HemodialysisDescription Process of separating certain cells from the plasma in the blood. Hemodialysis mimics the function of the kidneys.

It circulates blood through tubes made of semipermeable membranes to remove waste products and excess fluids.

Procedure Blood is taken from a patient's circulation and run through a cell separator (i.e. centrifuge) to separate blood plasma from blood cells and then returned to body without the plasma component. In some cases, plasma removed from the patient may be treated to remove antibodies and then returned to the patient. Otherwise (out of concerns for viral infection or allergic reactions) in the plasma exchange process, the removed plasma is discarded and the patient receives replacement plasma from a donor or saline solution with sterilized human albumin protein.

Blood is taken from a patient’s circulation and pumped by machine into a dialyzer. The dialyzer has two compartments separated by a thin semipermeable membrane. Blood passes on one side of the membrane and dialysis fluid on the other side. The waste and excess water passes through the membrane into the dialysis fluid, which is then discarded. The clean blood is returned to the patient’s circulation.

Indication Treatment of various immunological disorders requiring removal of disease-causing antibodies from the circulation in addition to pharmacological therapy

Extracorporeal removal of intravascular macroglobulins or immune complexes (pathogenic antibodies, cryoglobulins, myeloma light chains, immune complexes, endotoxins, and cholesterol-containing lipoproteins)

Removal of toxins such as those protein- or lipid-bound or red blood cells destroyed by toxin-induced hemolysis

Removal of blood proteins that are overly abundant and cause hyperviscosity syndrome

Acute dialysis: Acid/Base disorders Electrolyte

imbalance Intoxication Overload (fluid) Uremia

Chronic dialysis: Pericarditis Uncontrolled CHF

or HTN Peripheral

Neuropathy End Stage Renal

Disease

Anticoagulation

Heparin is widely used to prevent clot formation. Heparin is protein-bound and will be removed during the

procedure, therefore, requirements for heparin in TPE are higher than in hemodialysis.

It is recommended to maintain activated clotting times at 2 – 2.5 times baseline.

Heparin is widely used to prevent clot formation during hemodialysis.

Patients with higher risk of bleeding can be dialyzed without anticoagulation.

Time to complete treatment

The length of treatment depends on many factors (i.e. patient’s hemodynamic stability, hematocrit, blood and plasma flow rate)

Range: 1 – 4 hours (an exchange of 4L takes ~2 – 2.5 hours)

3 - 4 hour treatments (up to 5 hours for larger patients)

Treatments up to 3 times a week.

Vascular access

In a limb Central vein

Arteriovenous (AV) fistula AV graft Venous catheter (dual lumen)

Complications Fever due to contamination of dialysate or infection Hypotension and dehydration due to inadequate fluid

replacement or medication removal Electrolyte imbalance Hemorrhage, hemolysis Cardiac irritation from central line catheter and/or infusion

directly into right atrium Air embolism

Fever due to contamination of dialysate or infection

Clotting of dialyzer Graft or fistula site infection Vascular access dysfunction/clotting Vascular “steal” syndrome (low blood flow)

Factors affecting drug removal

The substance to be removed should be sufficiently large with a molecular weight (>15,000 Daltons). Otherwise, it could be removed by less expensive filtering such as hemofiltration or high-flux hemodialysis.

The substance to be removed must have a long half-life, such that extracorporeal removal is more rapid than the body’s normal clearance mechanisms.

The substance to be removed should be acutely toxic and/or

Drug physiochemical properties Small molecules (<500 Daltons) Clearance (inversely proportional to molecular

weight) Molecules with an ionic chargeWater solubility Water insoluble drugs remain in blood

compartment

6 Dialysis: Kidney Failure: Merck Manual Home Edition. Available at http://www.merck.com/mmhe/print/sec11/ch143/ch143d.html

7 Frequently Asked Questions. Apheresis Technologies, Inc., (ATI) accessed via http://www.apheresis.com/ques.html

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resistant to typical therapy; such that TPE’s rapid elimination from the extracellular fluid is indicated.

Protein binding Only free and unbound molecules can cross

the membrane and be removedVolume of distribution (Vd) Drugs with large Vd are not removed by HD Low tissue-bound drugs

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References:

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