Plasma exchange in Canada - NCBI

CURRENT REVIEW * ACTUALITES

Plasma exchange in Canada Gail A. Rock, PhD, MD; Gregory W. Tricklebank, MA; C. Ann Kasaboski, BSc; the Canadian Apheresis Study Group* Since 1982 the Canadian Apheresis Study Group (CASG) has collected data on plasma exchange activities in Canada. In 1987, 5907 such procedures were carried out on 700 patients for more than 22 different diseases; this represented an increase of 28% over the figure for 1982. A shift in activity has occurred over the years; originally hematologic disorders accounted for most of the procedures; however, in 1987, 60% of the exchanges were done to treat neurologic disorders, mainly myasthenia gravis and acute and chronic Guillain-Barre syndrome. Several prospective randomized clinical trials have recently been completed by the CASG in the hope of determining the optimal application of plasma exchange. These studies, currently under review, include 168 patients with multiple sclerosis, 100 with thrombotic thrombocytopenic purpura and 43 with rapidly progressive glomerulonephritis. Reactions occur in 12% of cases; they are usually minor and are limited to circumoral paresthesia, mild hypertension or hypotension and hives.

Depuis 1982 le Groupe canadien d'etude de l'apherese reunit des donnees sur l'epuration plasmatique au Canada. En 1987 on l'a pratiquee 5907 fois chez 700 sujets souffrant de plus de 22 maladies differentes, soit une augmentation de 28% sur l'annde 1982. Alors qu'au debut on y recourait surtout pour des troubles hematologiques, en 1987 les 60% des epurations sont faites pour traiter des maladies neurologiques, surtout la myasthenie grave et le syndrome de Guillain-Barre aigu ou chronique. Le groupe vient de terminer plusieurs essais cliniques prospectifs afin de connaitre le meilleur emploi de la plasmapherese et s'occupe actuellement a les analyser. Ils portent sur 168 cas de sclerose en plaques, 100 de purpura thrombotique thrombocytopenique, 43 de glomerulonephrite a evolution rapide. On note des effets ind6sirables dans 12% des cas, mais ils sont le plus souvent de peu de gravite: il ne s'agit que de paresthesie peribuccale, d'hypertension ou d'hypotension arterielle legtre, d'urticaire. *Members: Drs. Grenfell Adams, Department ofMedicine, St. John's General Hospital; Barrett Benny, Department of Hematology, Vancouver General Hospital; Victor Blanchette, departments of Hematology and Oncology, Hospitalfor Sick Children, Toronto; Noel Buskard, Department ofMedicine, University of British Columbia, Vancouver; Robert Card, Department ofMedicine, University Hospital, Saskatoon; William Clark, Department ofNephrology, Victoria Hospital, London, Ont.; Peter Ford, departments ofMedicine and Pathology, Queen's University, Kingston, Ont.; John Freedman, Blood Bank, St. Michael's Hospital, Toronto; Philip Gordon, Department of Haematology, University Hospital, Edmonton; Max Gorelick, medical director, Canadian Red Cross, Halifax; John Kelton, Department of Pathology, McMaster University, Hamilton, Ont.; John Klassen, Department ofImmunology, Foothills Provincial General Hospital, Calgary; Pierre Leblond, Department ofMedicine, hopital du Saint-Sacrement, Quebec; Mariette Lepine-Martin, Department of Hematology, Centre hospitalier universitaire, Sherbrooke, PQ Jack McBride, Department of Laboratory Medicine, Henderson General Hospital, Hamilton, Ont.; Phillip Mickelson, Health Services Directorate, Department of National Health and Welfare, Ottawa; Rama Nair, Department of Epidemiology and Community Medicine, University of Ottawa; Ken Shumak, departments ofMedicine, Pathology and Immunology, University of Toronto; Tsipora Shore, departments of Hematology and Oncology, St. Boniface General Hospital, Winnipeg; Robert Spasoff Department ofEpidemiology and Community Medicine, University of Ottawa; Marion Sternbach, Department of Hematology, McMaster University Health Sciences Centre, Hamilton, Ont.; and David Sutton, Department of Medicine, Toronto Western Hospital Dr. Rock is in the departments of Medicine, Pathology and Biochemistry, University of Ottawa, Mr. Tricklebank is with the Canadian Red Cross National Office, Ottawa, and Ms. Kasaboski is in the Department of Medicine, University of Ottawa.

Reprint requests to: Dr. Gail A. Rock, 206-435 St. Laurent Blvd., Ottawa, Ont. KIK 2Z8 CAN MED ASSOC J 1990; 142 (6)

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T herapeutic plasma exchange involves the selective removal of plasma from a patient and replacement with another appropriate fluid. The cellular components of the blood are returned with the replacement fluid to restore normal volume. Albumin, crystalloids or both are generally used to replace the plasma, the removal:return ratio being 1:1. Previously, fresh frozen plasma was frequently used as the replacement fluid; however, the risk of infection has now precluded such use except for the treatment of thrombotic thrombocytopenic purpura (TTP) and a few other disorders. "Apheresis" is a more general term, referring to the removal of any blood component. Early procedures, which involved manual separation of blood into its various components, were tedious and extremely time-consuming, requiring about I1/2 hours to remove 500 ml; therefore, plasma exchange was not widely used.' This has changed with the recent development of sophisticated and highly automated machines that enable a single volume exchange (involving a total of about 3 to 5 L of plasma) to be completed in only 2 to 3 hours. Two main types of machinery, with different techniques of separation of the cells and plasma (i.e., centrifugation and membrane filtration), are used. The machines operate by continuous flow or intermittent recycling principles, and various anticoagulants, including 4% sodium citrate, acid citrate dextrose with adenine, and heparin, are used. The extracorporeal volume ranges from 100 to 300 ml. Special measures are required to reduce volumes in pediatric cases.

How does plasma exchange work? The beneficial effects of plasma exchange depend on one or both of two postulated mechanisms: (a) the removal of some abnormal plasma constituent and (b) the replenishment of a normal plasma constituent in which the patient is deficient. The procedure can be compared to renal dialysis, but only small molecules and substances are removed from the blood during dialysis. New techniques involving specific absorbent and immunoaffinity columns permit direct removal of toxic compounds such as antibodies and low-density lipoproteins (LDLs). However, although promising, these techniques are currently experimental and still expensive: some of the absorbent columns add an extra $1000 per treatment.

change. In most cases the procedure will not affect the underlying cause of the disease; thus, its efficacy is limited to acute intervention. Several publications have summarized the indications for plasma exchange;'-5 among the relatively few accepted indications are hyperviscosity (including macroglobulinemia), myeloma, acute Guillain-Barre syndrome6 and myasthenia gravis, either in crisis7 or preoperatively. Because the incidence of many of these diseases is relatively low, multicentre trials are required to prove the efficacy of plasma exchange.

Risks Although generally well tolerated, plasma exchange is not totally benign. The overall rate of reaction in 10 000 cases, as reported to the Canadian Apheresis Study Group (CASG) registry, is about 12%;1 60% of the reactions are minor and transient and include nausea, circumoral paresthesia, mild hypertension or hypotension and hives. Other more serious side effects are not as easily managed and include cardiovascular distress, anaphylactic shock and certain disease-specific rebound effects. Dangerous side effects are uncommon. Although several deaths have been reported since 1979,9 no specific cause has been found. If plasma is used as the replacement fluid there is always the risk of allergic reactions or transmitted diseases such as hepatitis and acquired immune deficiency syndrome. Citrate toxicity must also be considered. The level of citrate in anticoagulated plasma is approximately 69 mM; albumin solutions also contain citrate, the concentration depending on the method of protein purification used.

Apheresis in Canada

The CASG was established in 1982 with the assistance of the Department of National Health and Welfare. The group is composed of 19 representatives from every major medical centre, including hematologists, nephrologists, rheumatologists, epidemiologists and statisticians. Several protocol groups representing areas of specific interest provide expert advice to the parent body. The CASG meets once a year to consider current activities, develop future trials and advise on protocols. The protocol groups meet as required and have developed several prospective, randomized trials funded by various granting agencies after peer review. Since 1982 the CASG has maintained a detailed record of all plasma exchange procedures in Canada Indications (Table 1), including information on the disease Any person with a disease in which an abnor- involved, the total number of exchanges, the number mality or deficiency of plasma constituents is impli- of exchanges per patient, the type of machine, the cated is theoretically a candidate for plasma ex- replacement fluid used and the number and type of 558

CAN MED ASSOC J 1990; 142 (6)

reactions. In presenting the registry data we have not been able to capture all of the information; a few small areas are known to have incomplete reporting. Thus, the total number of procedures is somewhat greater than reported here. Overall, the number of exchanges has increased, from 4616 in 1982 to 5907 in 1987 (Fig. 1). A

considerable increase was noted in 1985 because of the inclusion of certain neurologic and hematologic diseases.

Neurologic diseases More than 3300 plasma exchanges were carried

Table 1: Number of plasma exchange procedures performed in Canada from 1982 to 1987 by diagnosis Year; no. of procedures

Diagnosis Neurologic Acute Guillain-Barre syndrome Chronic Guillain-Barre syndrome Eaton-Lambert syndrome Multiple sclerosis Myasthenia gravis Hematologic ABO-incompatible bone marrow Agammaglobulinemia Autoimmune hemolytic anemia

Cryoglobulinemia Factor Vil antibodies Hemolytic-uremic syndrome Idiopathic thrombocytopenic purpura Leukemia Lymphoma Myeloma Pure red cell aplasia Rh hemolytic disease of the newborn Schonlein-Henoch purpura Sickle cell anemia Thrombocytopenia Thrombotic thrombocytopenic purpura Waldenstrom's disease

Collagen-vascular Dermatomyositis Mixed connective tissue disease Polymyositis Raynaud's disease Rheumatoid arthritis Sj6gren's syndrome Systemic lupus erythematosus Vasculitis Renal

Glomerulonephritis Goodpasture's syndrome Transplant rejection Miscellaneous Biliary cirrhosis Dermatitis herpetiformis Drug overdose Pemphigus Oter Total

1982

1983

1984

1985

1986

1987

223

262

309

481

570

904

351 4 91 682

487 7 215 645

571 41 40 726

633 20 37 824

466 19 285 665

754 25 692 973

7 0 63 102 25 63

7 2 20 87 17 45

15 4 15 80 11 48

7 0 37 101 13 54

5 0 16 127

5 0 10 86 12 153

114 1 8

234

230

1

4

3 103

11

7

1

16 215 14

159 3 0

161

124 0 6 94

150 8 0 0

151 6 0 2

147 90

374 312

471

11

153

174 15

207 6 0 258 14

1

126 0 0 0

208 10 0 0

43 8 2 0

250 518

335 382

714

238

339

453 292

0

7

16

6

12

6

0 39

41

23 28 30 15

32 25 45 10 2

19 29 34 5

0 19 25

347 0

22 31 43 89 7

5

1 4

414 171

504 109

559 73

527 112

522 120

248 43

102 81 130

180 175 111

163 112 88

150 250 70

164 279 38

79 136 45

152 0 3 30 457 4616

199 18 6 66 230 4686

76 13 0 8 372 4718

34 11 0

36 8 0 49 255 5345

29 9 1 48 367

41

0

29 201 5029

5907


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out for neurologic disorders in 1987, a 250% increase in 5 years. Such disorders now account for

Collagen -vascular diseases

60% of all exchanges. Early treatment reduces the length of hospital stay and the number of days on a respirator for patients with acute Guillain-Barre syndrome;6 results are variable among those with chronic disease.'0 The reason for the differences between the two diseases is not yet known. The dramatic increase in the number of procedures for the treatment of neurologic diseases is also a result of a current Canadian study of multiple sclerosis. With more than 3000 affected people in Canada,' ''i3 this disease represents the greatest potential source of demand for plasma exchange. The results of the study, which are in preparation, will determine whether future demand will level off or markedly increase.

In 1979 it was stated that 75 000 patients with rheumatoid arthritis might benefit from plasma exchange.'6 If translated into actual use this number would have taxed the resources of all apheresis units and the available blood supply. A study at Queen's University, Kingston, Ont., showed no benefit from plasma exchange.'7 As a result, although more than 300 procedures were done in 1982, virtually none have been done since the release of this study. Future interest in collagen-vascular diseases must involve an evaluation of the effectiveness of plasma exchange in systemic lupus erythematosus, which accounts for approximately 500 exchange procedures annually. A multicentre US trial was stopped because there was no significant improvement.'8 Patients with systemic lupus erythematosus continue to undergo plasma exchange for various reasons; as a result the CASG is contemplating a clinical trial.

Hematologic diseases Of 15 hematologic diseases listed with the CASG registry, only macroglobulinemia and some manifestations of multiple myeloma are considered to be accepted indications. Although the survival rate among people with myeloma is generally only 2 to 4 years after diagnosis,' the quality of life can be improved if plasma exchange is included as part of the treatment. Despite 200 to 300 patients being admitted to hospital each year with macroglobulinemia or multiple myeloma the number of plasma exchanges has increased only marginally since 1982, indicating reasonable containment of therapy. TTP has been the most common hematologic disease treated with plasma exchange. Exchange or infusion of fresh frozen plasma is now known to decrease the mortality rate significantly, from 80% to 30%, when combined with drug therapy.'4 '5 However, it is not yet clear whether plasma exchange is better than plasma infusion or why either method works. Although no specific recommendations have been made for hemolytic disease of the newborn due to Rh incompatibility the number of procedures carried out by the CASG was constant (about 150 per year) until 1987, when it decreased dramatically, to 43. Whether this decrease is a chance fluctuation or represents a decrease in disease incidence or severity must be determined. Increasingly hemolytic-uremic syndrome is being treated with plasma exchange. No clinical trial has been contemplated; however, the overall similarity to TTP may mean that the results of the TTP trial will be useful in choosing appropriate treatment. Other hematologic diseases frequently treated with plasma exchange include cryoglobulinemia and immune thrombocytopenia (ITP). 560


Renal diseases Goodpasture's syndrome, particularly with renal failure and pulmonary hemorrhage, is one of the accepted indications for plasma exchange; however, this was not determined by a randomized clinical trial. The rationale is the removal of antibodies to the glomerular basement membrane, even though it is known that the antibody level does not necessarily correlate with the extent of disease.'9 Without the procedure the death rate is 80% to 100%. Recent advances in immunosuppressive drug therapy have led to a decline in the use of plasma exchange for renal transplant rejection. A further deterrent has been the relatively poor response reported in some studies.20 Glomerulonephritis has accounted for between 100 and 200 exchange procedures annually. A Can6000

'R4000

j

-

1

1

0

1000 -

1982 1983

1984 1985

1986 1987

Year

Fig. 1: Total number of plasma exchange procedures in Canada by disease category from 1982 to 1987. Black area of bars represents neurologic diseases, cross-hatched area hematologic diseases, dotted area collagen-vascular diseases, diagonally striped area renal diseases and vertically striped area other diseases.

adian cooperative clinical trial involving patients with rapidly progressive glomerulonephritis (RPGN) was started in 1984 and has recently completed patient entry. The results can be expected to produce a difference of 100 procedures per year depending on the outcome.

Current clinical trials

addition of plasma exchange to other therapy improves the prognosis. Eligibility criteria included age from 4 to 75 years, normal-size kidneys, evidence of impaired renal function, as measured by the serum creatinine level and a renal biopsy. Patients were excluded if there was evidence of serious infection or active ulcer disease. A total of 43 patients were entered; in addition, information was collected on several ineligible patients.

The CASG has begun randomized prospective clinical trials of several disorders and maintains Multiple sclerosis study protocol groups that monitor activities in others. This prospective, placebo-controlled, blinded study was designed to determine if either of two TTP study immunosuppressive protocols together with plasma Started in 1983 this two-armed study compares exchange would result in sustained stabilization or plasma exchange and plasma infusion, in addition to clinical improvement in patients with progressive antiplatelet drugs, in the treatment of TTP. All disease. Eligibility criteria included a minimum age patients receive dipyridamole, acetylsalicylic acid of 15 years and clinically or laboratory-confirmed and fresh frozen plasma through exchange or infu- presence of progressive disease with scores between sion. The eligibility and exclusion criteria attempt to 4.0 and 6.5 on the expanded disability status scale.' ensure that only TTP patients able to receive these Patients were excluded if they had previously retherapies are entered. Data are also maintained on ceived chemotherapy or had illnesses that might be adversely affected by these treatments, were unwillthose who are ineligible. To be eligible for entry patients must have ing to continue with the study or were women thrombocytopenia (platelet count less than 100 x unwilling to avoid pregnancy for at least 24 months. 1 09/L), microangiopathic hemolytic anemia (erythro- Patients were randomly assigned to receive cyclocyte fragmentation present on peripheral blood phosphamide and prednisone alone, the two drugs smear), no identifiable cause for TTP (e.g., dis- and plasma exchange, or placebos and sham plasma seminated intravascular coagulation, carcinoma or exchange. This trial involves nine research clinics and the eclampsia) and no history of congestive heart failure or anuria sufficient to prevent tolerance of plasma CASG and is funded by the Medical Research Council of Canada. Its total patient accrual of 168 infusion. As of September 1989 patient recruitment was has been reached, and the results will be presented in complete: 43 nonrandomized patients for the sec- April 1990 at the annual meeting of the American ondary study and 100 randomly selected patients for Neurological Society. the primary study. The 6-month follow-up for final assessment is under way. This is the largest number Other trials of TTP patients ever accrued to one trial. The results The CASG continues to observe the use of are expected to help determine the treatment of this exchange in Canada and other countries and, plasma disorder. through various protocol groups, to review the need for additional studies or data collection. Several new ITP study trials are being contemplated. The CASG has a This proposed study will involve five centres particular interest in the use of new methods that and collect data on all patients with newly diagnosed permit the selective removal of substances from the ITP regardless of previous or future treatment. The plasma during perfusion so that the patient's plasma effects of therapy, including plasma exchange, will be can serve as the replacement fluid. At present such monitored so that within 2 years the CASG should methods are expensive and time-consuming, and in have invaluable material concerning the number and some cases they involve definite side effects. None type of treatments used in Canada and the relative the less, this is clearly the course to take since simple plasma removal is indiscriminate, with undefined effectiveness of plasma exchange. specificity. Further work is needed to elucidate the pathological mechanisms involved in the diseases RPGN study that respond to plasma exchange. Specific proceThis study, the data from which are under final dures can then be developed to permit removal of review, was designed to determine whether the only the offending materials. Early results of work CAN MED ASSOC J 1990; 142 (6)

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with anti-LDL and LDL absorbent columns, as well as the immune modulation caused by antibody binding to staphylococcal protein A columns hold promise.2223 However, much work needs to be done before widespread application will be possible.

Summary The past several years have been an active period for the practice of plasma exchange in Canada. The existence of the CASG has provided a unique opportunity for practitioners to share and respond to new developments in therapy and to assist in the formulation and implementation of practice guidelines. Because a large number of procedures have been carried out for certain indications without proven effectiveness, further clinical trials should be designed to determine the benefits of this expensive procedure. However, in some diseases, such as Goodpasture's syndrome and myasthenia gravis, the apparent benefit has made it difficult and, arguably, unnecessary to carry out randomized trials. The CASG will continue to encourage the exchange of information both in Canada and internationally. This will allow us to direct our activities and resources appropriately and permit further development and understanding in this exciting new field. The CASG and some of the clinical trials have been funded by the National Health Research and Development Program, Department of National Health and Welfare.

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2. The Safety. Efficac,y and Cost-Effectiveness of Therapeutic Apheresis (cat no OTA-HCS-23), Office of Technology Assessment, Washington, 1983

3. Nydegger UE, Vaudaux P, Castelli D: Trends in clinical hemapheresis 1986. Infusionsther Klin Ernahr 1987; 14: 4-6 4. Consensus Conference: The utility of therapeutic plasmapheresis for neurological disorders statement. JAMA 1986;

256: 1333-1337 5. Silberstein LE, Abrahm J, Shathl JJ: The efficacy of intensive plasma exchange in acquired von Willebrand's disease. Trans*fusion 1987; 27: 234-237 6. Guillain-Barre Syndrome Study Group, Johns Hopkins Uni-

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versity School of Medicine: Plasmapheresis and acute Guillain-Barre syndrome. Neurology 1985; 35: 1096-1104 7. Dau PC: Plasmapheresis therapy in myasthenia gravis. Muscle Nerve 1980; 3: 468-482 8. Sutton DMC, Nair RC, Rock GA et al: Complications of plasma exchange. Transfusion 1989; 29: 124-127 9. Huestis DW: Mortality in therapeutic haemapheresis [C]. Lancet 1983; 1: 1043

10. Dyck PJ, Daube J, O'Brien P et al: Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy. N Engl J Med 1986; 314: 461-465 11. Hospital MorbiditY, 1979-80, cat no 82206, Statistics Canada, Ottawa, 1984 12. Hospital MorbiditY, 1980-81, cat no 82206, Statistics Canada, Ottawa, 1987

13. Hospital Morbidity, 1982-83, cat no 82206, Statistics Canada, Ottawa, 1987 14. Bukowski RM, King JM, Hewlett JS: Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura. Blood 1977; 50: 413-417 15. Taft EG: Thrombotic thrombocytopenic purpura and dose of plasma exchange. Blood 1979; 54: 842-849

16. Wallace DJ, Goldfinger D, Gatti R et al: Plasmapheresis and lymphoplasmapheresis in the management of rheumatoid arthritis. Arthritis Rheum 1979; 22: 703-710 17. Dwosh IL, Giles AR, Ford PM et al: Plasmapheresis therapy in rheumatoid arthritis: a controlled, double-blind crossover trial. N Engl J Med 1983; 308: 1123-1129

18. Lewis E, Lachin J, Lupus Nephritis Collaborative Study Group: Primary outcomes in the controlled trial of plasmapheresis therapy (PPT) in severe lupus nephritis [abstr 511. Kidnev Int 1987; 31: 208 19. Lockwood CM, Rees AJ, Pearson TA et al: Immunosuppression and plasma-exchange in the treatment of Goodpasture's syndrome. Lancet 1976; 1: 711-715

20. Cardella CJ, Sutton D, Uldall PR et al: Intensive plasma exchange and renal-transplant rejection [C]. Lancet 1977; 1: 264 21. Kurtzke JF: Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurologi' 1983; 33: 1444-1452 22. Goding JW: Use of staphylococcal protein A as an immunologic reagent. J lInmunol Methods 1978; 120: 302-311

23. Stoffel W, Borberg H, Greve V: Application of specific extracorporeal removal of low density lipoprotein in familial hypercholesterolaemia. Lancet 198 1; 2: 1005-1007