Small Volume Plasma Exchange (SVPE) for Guillain-Barré Syndrome (GBS) Patients
Small Volume Plasma Exchange (SVPE) for Guillain-Barré Syndrome (GBS) Patients
Guillain-Barré syndrome (GBS) is the commonest form of acute flaccid paralysis and the
 incidence is high in low-income countries. In Bangladesh, most GBS patients are poor.
 Therefore patients cannot afford expensive specific treatments like intravenous
 immunoglobulin (IVIg) or plasmapheresis (PE) in part explaining the high mortality and
 disability compared to treated patients in high-income countries. Added difficulty in
 traditional PE is its unavailability and specialized device and manpower dependency. Most
 research in GBS has been conducted in high-income countries, largely in patients with a
 demyelinating form of GBS. Axonal form of GBS is common in low-income and Asian countries
 which has a different pathogenesis, clinical course and outcome than the demyelinating form.
 Very few therapeutic studies have been conducted in low-income countries due to expensive
 existing modalities of treatment. Here, the investigators propose SVPE as a treatment for GBS
 in patients from low-income countries. SVPE is relatively cheap, can be done at the bedside
 without any special device or electricity and eventually is expected to help poor severely
 affected GBS patients in underdeveloped and developing countries. The main outcomes will be
 the safety and feasibility of SVPE since this is yet to be established in the resource
 limited settings. To be able to evaluate the safety of SVPE, additional information will be
 acquired about the frequency of complications in non-GBS patients with a central line,
 treated during the same time period at the same study facility as the GBS patients. Severe
 sepsis due to central line associated blood stream infection and deep venous thrombosis in
 the limb where the central venous catheter will be inserted during or following the SVPE
 procedure, will be defined as severe adverse effect (SAE) and will be considered as primary
 outcome measure for safety. Blood, cerebrospinal fluid and other relevant biological
 specimens will be analysed for diagnosis and screening for infections. In addition clinical
 and neurological outcome assessment will be monitored until discharge of the patient from the
 hospital and up to four weeks since study entry. Confirmation of feasibility and safety, will
 eventually lead to a randomized control trial in future with a primary focus on the clinical
 efficacy of SVPE for the treatment of GBS in developing countries as an alternative for the
 conventional treatment with IVIg or PE.
Study design:

 In this safety and feasibility study, 20 GBS patients will be enrolled for SVPE as per
 protocol criteria. Clinometric measurements (heart rate, blood pressure, temperature, oxygen
 saturation (SpO2), neurological examination) along with documentation of central line
 associated blood stream infection (CLABSI) and other complications related to central venous
 (CV) catheter will be conducted daily and throughout the course of SVPE until the 2nd day of
 the withdrawal of the CV catheter according to a predefined protocol. Diagnosed or strongly
 suspected CLABSI and central venous catheter related deep venous thrombosis (DVT) will be
 followed up for definite outcome to determine the frequency of severe adverse events
 attributed to CLABSI until the patient discharges from the hospital. Neurological outcome
 will be documented according to several disability assessment scales throughout the SVPE
 until discharge and up to four weeks from the enrollment of the GBS patients. In addition,
 the safety of the SVPE in GBS patients will be compared with the background complication risk
 by determining the frequency of complications in non-GBS patients treated with a CV catheter
 at the same intensive care unit (ICU) during the same period using the same protocol for
 surveillance as in SVPE-treated GBS patients.

 SVPE kit:

 SVPE kit will be prepared with one blood transfusion set and two saline infusion sets
 connected with a tri channel device. On the other end the blood transfusion set will be
 connected with the blood bag, one saline infusion set is connected with 1 liter normal saline
 mixed with 2500 unit of un fractionated heparin and one saline infusion set is connected with
 500 ml hexa-ethyl starch solution. All the tubes should be made air free by fluid column from
 respective bag. The tri channel is then attached to the central venous catheter.

 Procedure of SVPE for GBS patients:

 After the SVPE set is prepared, patient's whole blood will be drawn from central venous
 catheter according to body weight (7 ml/kg) in each session in the blood transfusion bag with
 gravitation force placing the blood bag below central venous catheter tip level.

 The blood column in the transfusion set and in the central venous catheter will be cleared
 with normal saline mixed heparin solution attached previously through the side channel. The
 blood bag will be hung beside the patient in a saline stand uninterrupted to separate the
 plasma and blood cells which will eventually take 2.5 hours with gravitation. Blood cells
 will be infused back to the patient and plasma will be discarded and replaced by Fresh Frozen
 Plasma (FFP) and colloid solution alternately in equal volume through the side channel. One
 blood bag will be used each day for 6 sessions. At the beginning of each session 70 ml of
 heparin solution will be taken in the blood bag from the heparin mixed normal saline as
 anticoagulant. Six sessions will be done daily for consecutive 8 days. A total of 48 sessions
 will be done in eight days. These six sessions of small volume plasma exchange per day in an
 adult patient will remove approximately 1200 ml of plasma daily and eventually 9600 ml of
 plasma will be removed in total 48 sessions. All connection ports and tri channels of the
 central venous catheter, the blood bag and the saline bag are disinfected by using alcohol
 70% then dried on air before sampling blood or (dis)connection. These procedures are
 performed aseptically. Internationally, endorsed guidelines on central venous catheter blood
 stream infection prevention is followed throughout the entire period of the SVPE procedure.
 Total active interference with the patient in each session will be 30 minutes and total daily
 active interference with the patient will be three hours with a Daily schedule at 8AM, 11AM,
 2PM, 5PM, 8PM and 11PM. Plasma replacement will be done alternately using fresh frozen plasma
 and colloid solution (Hexa ethyl starch).

 Anticoagulation therapy:

 A loading subcutaneous low molecular weight heparin (1.5 mg/kg) will be given at least two
 hours before the onset of SVPE. Thereafter daily maintenance dose of subcutaneous low
 molecular weight heparin (1.5 mg/kg) will be continued for eight days or until SVPE
 completed.

 Indication of anti-platelet therapy:

 Patients with excessive clotting tendency despite receiving low molecular weight heparin will
 be subjected for evaluation of platelet activation. If the bleeding time is reduced by >50%
 of the baseline of the particular GBS patient, investigators will introduce anti-platelet
 medication. A loading oral dose of aspirin (500 mg) and clopidogrel (600 mg) will be given at
 least two hours before the next session of SVPE. Thereafter daily maintenance dose of oral
 aspirin (150 mg) and clopidogrel (75 mg) along with subcutaneous low molecular weight heparin
 (1.5 mg/kg) will be continued for eight days or until SVPE completed.

 Documentation of SVPE procedure:

 To define the safety of SVPE, the six daily sessions of SVPE will be documented in terms of
 duration and amount of the plasma removed in each session, type and volume of replacement
 fluid and fresh frozen plasma used, and any inconvenience compromising the SVPE sessions
 temporarily or permanently. Any difficulties hampering SVPE, which currently cannot be
 anticipated, will be documented as verbatim.

 Documentation of hemodynamic parameters and autonomic disturbance:

 Throughout the procedure, haemodynamic status including blood pressure, heart rate, any
 cardiac arrhythmia, oxygen (%) saturation in peripheral blood, fluid intake and output will
 be monitored daily as per standard practice in all ICU patients. Blood coagulability will be
 monitored with prothrombin time (PT) and bleeding time (BT) every alternate day. Autonomic
 parameters will be documented daily as per the presence of high or low blood pressure,
 increased or decreased pulse rate, orthostatic hypotension, cardiac arrhythmia, bladder and
 gastrointestinal dysfunction, pupillary abnormality, unusual sweating or hyper salivation.

 Documentation of infection:

 Features of infections including pyrexia, leukocytosis in peripheral blood, C-reactive
 protein and evidence of focal infections like positive blood, throat/tracheal aspirate or
 urine culture for pathogenic organisms etc. will be documented per protocol as per respective
 standard case record forms for specific hospital acquired infections (HAI). Clinical and
 laboratory evidence of HAI especially CLABSI will be monitored and explored at anytime during
 the SVPE procedure until the second day of withdrawal of the central venous catheter. A
 definite or strongly suspected CLABSI will be followed up until discharge to document the
 ultimate fate.

 Documentation of HAI and complications:

 An infection is considered HAI if all elements of a Centers for Disease Control and
 Prevention/National Healthcare Safety Network (CDC/NHSN) site - specific infection criterion
 are all present on or after the third calendar day of admission to the facility. Any
 infection before the third calendar day of admission will be considered as infection present
 on admission, except in case of CLABSI; which can occur even on day two of central venous
 catheter insertion. CLABSI, primary and secondary bloodstream infections sepsis and severe
 sepsis will be the main focus for infection documentation. All the patients eligible as per
 the enrolment criteria for CLABSI surveillance will be monitored from admission to the ICU.
 Ventilator associated pneumonia and catheter associated urinary tract infection will also be
 monitored using established guidelines in order to have a more specific rate of CLABSI and
 related complications. Appropriate clinical data, imaging, specimens for biochemical and
 microscopic examination and culture will be documented at specific time points defined as per
 specific HAI check list . Device associated complications include central venous catheter
 occlusion, haemorrhage and deep venous thrombosis. All these safety margin indicators will be
 defined as per specific guideline definitions.

 Use antimicrobial agents:

 Any infection will be treated by antimicrobial agents accordingly. Choice of the antibiotics
 (oral or intravenous) will be based on the site of infection, specific organisms isolated
 and/or severity of the infection reflected in clinical and laboratory features of systemic
 inflammatory response (raised total white blood cell (WBC) count (>11,000/c mm of blood),
 C-reactive protein (>40 mg/L) or positive culture of pathogenic organisms) and choices are
 made after consultation of a microbiologist. Appropriate lower generations of antibiotics for
 predicted site specific infection will be administered first if necessary before considering
 subsequent higher generations until the culture sensitivity report is available.

 Indications for withholding plasma exchange:

 1. Development of severe or terminal concurrent medical illness

 2. Hypotension (30 mm Hg decrease of systolic blood pressure or systolic blood pressure<90
 or mean arterial pressure (MAP)<65mm Hg) after start of treatment

 Indications for resuming plasma exchange:

 1. Return of blood pressure to baseline or systolic blood pressure>90 or MAP<65.

 2. After management of anaphylactic reaction following FFP or saline infusion.

 Indications for replacement of central venous catheter (CVC) to another site:

 1. CLABSI or catheter insertion site infection associated with CVC is diagnosed or strongly
 suspected as per protocol.

 Indications for guide wire replacement of central venous catheter (CVC) to the same site:

 1. Complete CVC occlusion despite anticoagulant or thrombolytic administration in absence of
 features of CLABSI

 Indication for blood transfusion:

 1. Anemia with hemoglobin concentration below 7 gm/dl during and after the SVPE procedure.

 When to stop the trial (Stopping rule):

 For feasibility purpose: A predictive success rate of 75% will be set regarding the SVPE
 procedure. If in more than 5 out of 20 SVPE procedure violates the protocol, the procedure
 will be considered not feasible and modification of the SVPE procedure will be considered
 before any further re-evaluation of modified procedure for feasibility along with safety.

 For safety purpose: A prior distribution of the success rate with regard to severe adverse
 effect (SAE) will be set as 75%. The investigators will consider severe sepsis due to CLABSI
 and venous thrombosis related to CVC use as SAE. If >5 patients had SAE at or before
 completion of SVPE in 20 GBS patients; the study will be stopped. Otherwise an RCT will be
 planned subsequently to evaluate the neurological efficacy of the SVPE procedure.

 Baseline documentation and Initial screening:

 Complete blood count including haemoglobin in g/L, total and differential WBC and platelet
 count and erythrocyte sedimentation rate (ESR), C-reactive protein, prothrombin time, serum
 creatinine, serum bilirubin and serum glutamic-pyruvic transaminase (SGPT) will be documented
 as baseline status for GBS patients with SVPE along with screening for hepatitis B, C and
 HIV.

 Documentation of anti-ganglioside antibodies:

 Serum concentration of anti-ganglioside antibodies (GM1 and GD1A) will be measured at the
 beginning and at the end of SVPE to observe the trend in titre change in the serum of GBS
 patients.

 Documentation at the end of SVPE:

 On the second day after removal of the central venous line, baseline documentations will be
 re evaluated. These include complete blood count including haemoglobin in g/L, total and
 differential WBC and platelet count and ESR, C-reactive protein, prothrombin time, serum
 creatinine, serum bilirubin and SGPT.

 Assessment of neurological function:

 Neurological examination will be performed to see the clinical trend of motor, sensory &
 autonomic parameters before, during the procedure and subsequently in the follow up of the
 patients up to four weeks.

 Assessment of Motor function:

 Different clinical assessment scales will be used to monitor changes in motor function. These
 are the GBS disability Score, Medical Research Council (MRC) sum score, Rasch-built MRC
 score, Overall Neuropathy Limitation Scale (ONLS), Rasch-built Overall Disability Score
 (R-ODS).

 Sensory function:

 Somatic and Gnostic sensation over the limbs will be examined bilaterally. Somatic sensation
 will be evaluated by examining fine and crud touch and pain sensation over the specific
 dermatomal regions and gnostic sensation will be evaluated by position & vibration sense.

 Autonomic function:

 Autonomic parameters will be documented as per the presence of high or low blood pressure,
 increased or decreased pulse rate, cardiac arrhythmia, bladder and gastrointestinal
 dysfunction, pupillary abnormality, unusual sweating, hyper salivation and abnormality in
 hair growth.
Inclusion Criteria:

 -  fulfill the diagnostic criteria for GBS patients of the National Institute of
 Neurological and Communicative Disorders and Stroke (NINDS) [19]

 -  ≥ 18 years of age at diagnosis

 -  unable to walk unaided for more than 10 meters (GBS disability score ≥ 3)

 -  included within 2 weeks of onset of weakness

 -  unable to afford standard treatment with IVIg or standard PE

 -  Informed written consent

 Exclusion Criteria:

 -  previous severe allergic reaction to properly matched blood products

 -  evidence of healthcare associated infection present on admission (except aspiration
 pneumonia)

 -  severe concomitant illness or terminal underlying disease

 -  pregnancy