Small Volume Plasma Exchange (SVPE) for Guillain-Barré Syndrome (GBS) Patients
Condition: Guillain-Barré Syndrome
MeSH terms: Guillain-Barre Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Small Volume Plasma Exchange
Intervention type(s): Procedure
Intervention description(s): Six sessions will be done daily for consecutive 8 days (total 48 sessions). 7 ml/body weight blood will be drawn at each session and will be separated into plasma and blood cells. Blood cells will be infused back to the patients and plasma will replaced by equal volume of fresh frozen plasma and colloid solution. At the end of each day 1200 ml plasma (total 9600 ml in 48 sessions) will be removed.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: SVPE; intravenous immunoglobulin; plasmapheresis