Safety and efficacy of therapeutic membrane plasmapheresis in the treatment of Guillain–Barré syndrome: A study from a tertiary care hospital from India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_907_15
Source of Support: None, Conflict of Interest: None
Background: Reports on therapeutic plasma exchange (TPE) with the standard hemodialysis equipment are scarce, particularly from developing countries.
Keywords: Acute inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome, hemodialysis, plasma exchange, plasmapheresis, therapeutic plasma exchange
Therapeutic plasma exchange (TPE) or plasmapheresis is an extracorporeal blood purification technique designed for the removal of large-molecular weight substances. Examples of these substances include pathogenic autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxins, and cholesterol-containing lipoproteins. Over the past 4 decades, it has been used to treat a variety of neurological, hematological, rheumatological, and renal disorders; its use has also become more extensive. Techniques for plasma separation from the remaining whole blood are either centrifugation or a membrane plasma separator (MPS). Traditionally, the plasma exchange was performed with centrifugation devices used in blood-banking procedures. These devices offer the advantage of allowing for selective cell removal (cytapheresis). This equipment is large and heavy, expensive, requires trained personnel and is not portable. The number of centers that can afford and utilize these devices is limited, and patient selection is restricted. The centrifugal plasma separation techniques used clinically do not produce a clear separation of plasma from cells. Blood cell losses, particularly of platelets, are significant.,
MPS is derived from the technology used in dialysis. Hollow-fiber filters for MPS look very similar to dialysis filters. TPE can also be performed with a hollow-fiber MPS filter connected to the blood pump and pressure monitoring system of the hemodialysis machine. The machine is used in its “isolated” ultrafiltration mode, bypassing the dialysate proportioning system. Compared to the traditional centrifugal technique, TPE with standard hemodialysis equipment is technically easier, faster, and has a smaller-sized equipment,, but is equally efficacious., Although TPE is generally regarded as a safe procedure, complications do occur.
TPE is a well-established therapeutic procedure commonly used in many neurologic disorders of autoimmune origin. It is considered that the beneficial effects of plasmapheresis occur through the removal of inflammatory mediators, including autoantibodies, complement components, and cytokines. Guillain–Barré syndrome (GBS), myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), and demyelinating polyneuropathy with IgG/immunoglobulin A are considered category I indications by the American Society for Apheresis. Reports on membrane filtration-based TPE are scarce, particularly from developing countries., We undertook a retrospective review to determine the safety and efficacy of this procedure in GBS, the most common indication for performing this procedure at our institution.
Records of all TPE procedures performed at our Hemodialysis Unit over a period of 5½ years (November 2009 to April 2015) were reviewed for indications, details of procedure, and outcomes. The study included adult patients who developed acute onset of flaccid quadriparesis and were diagnosed with GBS, as per the Brighton Working Group clinical case definitions criteria. In all patients, close monitoring of the respiratory, cardiac, and hemodynamic function was done. An early assessment and careful monitoring of swallowing was performed to identify patients at risk for aspiration and the need for the placement of a nasogastric tube. Careful watch of the breath-holding time and single-breath counting time was done for an early identification of patients requiring assisted mechanical ventilation. Prophylaxis for deep vein thrombosis, bladder and bowel care, physiotherapy, and psychological support was provided. Subcutaneous fractionated heparin and support stockings were used in all patients until they were are able to walk independently. The clinical course was described by using the GBS disability scale: 0, A healthy state; 1, Minor symptoms and capable of running; 2, Able to walk 10 m or more without assistance but unable to run; 3, Able to walk 10 m across an open space with help; 4, Bedridden or chair bound; 5, Requiring assisted ventilation for at least part of the day; and 6, Dead.
TPE was done by the MPS technique in which blood was filtered across a polysulfone membrane filter (PlasmaFlux, Fresenius) with a surface area of 0.6 m 2 and a standard hemodialysis machine [Nipro (Surdial) and Laser Cil 2000] was used in its ultrafiltration, dialysis-bypass mode. Vascular access was realized through a double-lumen hemodialysis catheter placed in the femoral or internal jugular vein. Blood flow rate was 100–150 ml/min and transmembrane pressure was below 100 mmHg. Heparin in an initial loading dose of 50 U/kg followed by bolus dose of 1000 U at 1 h was used. The filtrate of plasma was achieved by adjusting the height of the plasma filter, which was collected in a sterile plastic bag on the ground. An equivalent plasma replacement was done with crystalloid solution initially, followed by 4% human albumin in normal saline. At the end of each session of plasmapheresis, 2 units of fresh frozen plasma were administered. The schedule for plasmapheresis was one plasma volume (40 ml/kg) daily for 2 days, and then on alternate days. The daily assessment of muscle strength and motor performance was done, and TPE was discontinued once the ability to walk unaided was attained. All the adverse events/complications were recorded for safety analysis. The cost of each session of treatment was calculated. An informed consent for the procedure was obtained for all patients. The study was approved by the institutional ethics committee.
Descriptive statistics including means, standard deviation, and percentages were used to describe the demographic and clinical data. For a comparative analysis, the minimal muscle power in either proximal or distal half of the limb was used. The paired samples t-test with 95% confidence interval (95% CI) was done to compare the mean changes in power in the extremities (the Medical Research Council scale) and the changes in the GBS disability grade (DGD) from admission to discharge. A difference was considered significant when the P value was less than 0.05. Statistical analyses were carried out using the Statistical Package for the Social Sciences, version 16 (SPSS, Chicago, IL, USA).
Over the study period, 35 patients underwent TPE at our unit. Thirty one patients with GBS were included in the study. Four patients, one each with MG, systemic lupus erythematosus with autoimmune hemolytic anemia and thrombocytopenia, postpartum hemolytic uremic syndrome, and neuromyelitis optica were excluded.
Demographics and clinical characteristics
[Table 1] shows the demographic and clinical characteristics of the study patients. The mean age of the patients was 45.8 ± 18.3 years (range 18–85 years). Twenty one (67.7%) patients were males and 10 (32.3%) were females. The mean duration of illness at admission was 7.8 ± 6.3 (range 2–35) days. On examination, all (100%) patients had generalized areflexia (GA), 5 (16.1%) patients had autonomic dysfunction, and 6 (19.4%) patients had associated cranial nerve palsy. The mean grade of power in the upper limbs was 2.4 ± 1.2 and in the lower limbs was 1.5 ± 1. All patients were nonambulatory at admission. Five (16.1%) patients had respiratory involvement and 2 had severe respiratory weakness necessitating mechanical ventilation. One (3.2%) patient had a history of prior failed course of intravenous immune globulin (IVIG) treatment. Electrodiagnostic studies done in 11 (35.5%) patients revealed acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 9 (29%) and predominant changes suggestive of acute motor axonal neuropathy (AMAN) in 2 (6.5%) patients [Table 1]. Eleven (35.5%) patients fulfilled Brighton level 1, and 20 (64.5%) patients fulfilled level 2 diagnostic certainty criteria.
Plasmapheresis and complications
A total of 120 TPE sessions were performed in these patients. Each patient underwent a mean of 3.8 ± 1.5 (range 1–9) TPE sessions. Each session of plasma exchange took 1.5 to 2 h. Approximately 2200 to 2500 ml of plasma was extracted in each session.
The complications observed during TPE were: hypotension in 12 (10%), accelerated hypertension in 3 (2.5%), chills and rigors in 5 (4.2%), bleeding in 5 (4.2%), and filter clotting in 6 (5%) sessions. These were minor in nature and were appropriately treated. Serious complications were observed during 2 (1.7%) sessions. One patient experienced an anaphylactoid reaction to albumin infusion requiring termination of plasmpheresis and one patient survived a cardiorespiratory arrest after a TPE session possibly due to arrhythmia from an associated autonomic dysfunction. Three patients had complications of infection. Two patients developed aspiration pneumonia due to pharyngeal weakness, and 1 patient developed catheter site infection. These were successfully managed with antimicrobial agents.
The medical and paramedical staff of the renal unit conveniently and quickly adapted to the TPE procedure, and were equally at ease in carrying out TPE similar to the hemodialysis procedure.
The cost of each session of plasmapheresis excluding the cost of equipment and hospital service charges was calculated to be USD 415.
One (3.2%) patient died. The patient had severe autonomic dysfunction resulting in hypotension requiring vasopressor therapy. She developed respiratory failure requiring mechanical ventilation on the next day of the first TPE and died 1 day later due to progressive deterioration. Thirty (96.8%) patients survived and recovered. The mean duration of hospital stay was 13.6 ± 4.7 (range 5–26) days [Table 1]. At discharge, there was a significant improvement in grade of power in both upper and lower extremities [Table 2]. The grade of power in upper limbs increased from 2.4 ± 1.2 at admission to 4.2 ± 0.5 at discharge showing an increase of 1.7 ± 1.2 (95% CI, 1.3 to 2.1, P= 0.001). In lower limbs, the grade of power increased from 1.5 ± 1 at admission to 3.9 ± 0.6 at discharge showing an increase of 2.4 ± 0.9 (95% CI, 2.1 to 2.7, P= 0.001). The GBS disability grade was reduced from 4 ± 0.6 on admission to 2.1 ± 0.6 at discharge showing a mean difference of 1.9 ± 0.7 (95% CI, 1.6 to 2.2, P= 0.001) [Table 3]. Twenty-four (77.4%) patients were able to walk unaided at discharge compared to none at admission. Six (19.4%) patients who were not ambulatory at discharge had significantly lower grade of power in lower limbs (P = 0.05) at admission and all had respiratory muscle involvement compared to those who were ambulatory at discharge. There was no significant difference in the demographic and other clinical characteristics. On follow-up, all patients had recovered fully.
Results of our study suggest that membrane-based TPE with standard hemodialysis equipment is a safe and effective procedure for the treatment of severe GBS. All our patients had severe GBS, and all but one (96.8%) had a successful outcome. After having received a mean of 3.8 ± 1.5 TPE sessions, the patients had a significant improvement in the grade of power in the extremities over a median of 2 weeks. Majority of the patients (77.4%) were able to walk independently at discharge as compared to none at admission. All the patients had full recovery at follow-up visits. In non-ambulatory patients with GBS, plasmapheresis is most effective when it is started within the first 2 weeks of disease onset. The median duration of the disease in our study was 1 week. Only 2 patients had it for more than 2 weeks. Early institution of TPE was an important factor for the favorable response seen in our patients.
Although the use of membrane-filtration PE represents a valuable and relatively safe therapy, some life-threatening reactions do occur. When carried out by experienced staff, TPE is a relatively safe procedure. Rate of TPE-related complications was found to be comparative with those reported in the literature.,, Majority of the complications were minor in nature and were appropriately treated. Even the serious complications were successfully managed. Mortality seen in 1 patient was not likely to be related to the TPE procedure. The patient had a severe autonomic dysfunction and respiratory failure and died due to the severity of the illness.
The duration of 1.5–2 h for one membrane-based TPE session in our study was faster compared to 5–6 h per procedure required for centrifugal plasma separation techniques used in blood banks.,
GBS is the most frequently occurring clinical paralytic disorder, with an annual incidence of 1–2 per 100,000 persons. It is a dangerous disease because up to 30% of the affected patients require mechanical ventilation, approximately 20% remain severely disabled, and approximately 5% die despite immunotherapy. As per the guidelines of the American Academy of Neurology (AAN), plasma exchange or IVIG hastens recovery from GBS. Both the modalities are equivalent in their beneficial effects. The AAN recommends plasma exchange for nonambulatory adult patients with GBS who start treatment within 4 weeks of the onset of neuropathic symptoms. It is also recommended for ambulatory patients who start treatment within 2 weeks of the onset of neuropathic symptoms. The IVIG therapy is recommended for nonambulatory adult patients with GBS who start treatment within 2 or possibly 4 weeks of the onset of neuropathic symptoms. Due to its ease of administration and wide availability, IVIG is frequently the preferred treatment. In GBS patients, the direct cost of IVIG therapy was found to be more than twice that of TPE. Given equivalent efficacy and similar severity and frequencies of adverse events, TPE appears to be a less expensive first-line therapy option for treatment of patients with GBS. Moreover, in developing countries like India, despite its availability, the cost of IVIG is prohibitive. The cost of 4 TPE sessions was calculated to be 1660 USD in our study, which is economical as compared to 3333–4166 USD market cost of a course of IVIG.
If infrastructural facilities exist, plasma exchange is a cheaper option. However, a huge initial investment is required to setup a plasma exchange unit. Centrifugation-based TPE is utilized infrequently due to the limited availability of the equipment and reliance on blood bank services. Furthermore, there is a need for procuring and periodically renewing permissions and licenses from regulatory authorities for providing plasma exchange. Hemodialysis services are available at most referral tertiary care centers, and existing capabilities can be conveniently used to provide membrane-based TPE. In medical conditions that also require hemodialysis, this can follow TPE without the need for additional equipment or training of staff. With minor innovations, both procedures can be done simultaneously (tandem hemodialysis–plasma exchange), reducing procedure time and costs.
Although this study has limitations of being a single centre, retrospective study with comparative less number of patients, the results of this study are in concordance with those previously published. Further, it highlights that, in developing countries, existing hemodialysis facilities can be conveniently adapted to provide membrane-based TPE. Therapeutic membrane plasmapheresis using adapted hemodialysis equipment is a simple, low cost, therapeutic alternative. It can be safely delivered by the medical and paramedical staff working in hemodialysis units. As hemodialysis machines are easy to transport, this makes it the most practical method for conducting plasmapheresis in tertiary care hospitals.
Therapeutic membrane plasmapheresis is a safe and effective procedure. It can be conveniently delivered with standard hemodialysis equipment. Existing hemodialysis facilities can be conveniently utilized to provide membrane-based TPE. In developing countries, membrane-based TPE is an economical option, and may be offered as the treatment of first choice in autoimmune disorders such as GBS.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]