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This report is being filed to provide additional information in h.6 and h.11.Investigation: since this was a journal publication to assess extracorporeal photopheresis in paediatric patients: a retrospective comparison between different 'off-line' protocols involving 91 patients between september 2006 and november 2019, the lot numbers were not requested; therefore, a disposable lot history search could not be conducted.The authors included all the apheresis procedures from september 2006 to november 2019 in which they had the data to perform the analysis (n = 1517).All collections were performed with an ¿off-line¿ method.Apheresis procedures for mnc collection were performed either with the cobe spectra or spectra optia system.Initially, used cobe spectra (terumo bct, lakewood, co) on either the autopbsc: 6.1 pbsc or cmnv7 program.More recently, we switched to the spectra optia device (terumo bct), using either the mnc2 or cmnc program.For these procedures, the team of nurses followed device and protocol specific manufacturer instructions.The applied settings in spectra optia to collect the lymphocytes are as follows: flush and chase volumes of the mnc program were set at 16 ml and 4 ml, respectively.For cmnc procedures, collection pump flow rate was set at 1 ml/min and collection preference was adjusted to a collection line haematocrit of 2%.We usually processed between 1 and 2 blood volumes to collect mncs.The collected product was diluted to a volume of 300 ml by adding saline, and subsequently 3 ml of 8-mop aqueous solution (gerot pharmaceutika, vienna, austria) was added to achieve a final concentration of 200 ng/ml.This final product was then transferred to a uva-permeable bag (macopharma, tourcoing, france), exposed to uva irradiation (uvmatic irradiator, vilbert lourmat, france) at a dose of 2 j/cm2 and immediately reinfused.In patients with body weight <15 kg, the blood cell separator is primed with packed red blood cells, and the final collected product is concentrated to 150 ml.Anticoagulant citrate dextrose formula-a is used as an anticoagulant at a ratio of 14/1 or 12/1.Intravenous calcium is usually used as prophylaxis as per institutional protocol.Collection efficiency (ce) was calculated using the following formulas: ce1(%): product total lymphocytes/(pre-apheresis + post-apheresis lymphocytes/2) x processed volume ce2(%): product total lymphocytes/pre-apheresis lymphocytes x processed volume platelet loss: 100 - (platelet count after the collection x (100/platelet count before collection)) haematocrit loss: pre-collection haematocrit ¿ post-collection haematocrit.Safety data were collected on all leukocytapheresis procedures (n = 1524).A total of 1517 ecp procedures were included in the analysis comparing devices and programs: 71 were performed with the cobe autopbsc 6.1, 868 with the cobe spectra cmnv7, 204 with the optia mnc2 and 374 with the optia cmnc.The average time of collection was 157 min.The adverse events were recorded in all the leukocytapheresis procedures (n = 1524).The most frequent collection-related adverse events concerned venous access in 329 (21.7%).Most procedures (930 of them, which represents 61%) were performed using a catheter placed in the femoral vein followed by the jugular (19.9%); only 8.1% of procedures were performed through peripheral veins.The catheter related adverse events recorded were as follows: need to change return/access line in 214 of 329 procedures (65%); catheter flushing in 165 procedures (50.5%); use of urokinase anticoagulation to achieve the adequate flow rate in 104 (31.6%); infection in 48 (14.5%); and haematoma or pain in 10 (3%).Only one patient developed severe hypotension and fever (most likely secondary to infection).Additionally, citrate toxicity was recorded in 6.2% of all procedures, causing episodes of paraesthesia, nausea or vomiting related to mild hypocalcaemia.Median levels of haematocrit and platelet loss were 2.9% (0.7¿4.7) and 28.6% (15.7¿39.2), respectively.Transfusion support consisted of packed red blood in 20.1% of collections and platelet support in 11.8%.However, it is important to mention that most procedures were well-tolerated, and only one required interruption due to an adverse event (severe hypotension and fever as mentioned above).In our study, the most frequent adverse events were those related to the catheter, as reported elsewhere.In the literature, the most common complication related to access was infection (0%¿42%) followed by abnormal clotting.In our series, the most frequent adverse event was minor, involving a need to change return/ access; other authors may not have considered this to constitute an adverse event.Catheter infection was quite frequent, contrasting with previously published data from our group on stem cell donors.However, it is important to point out that most catheters were used in the context of transplantation and for longer periods of time than those involved in progenitor cell collection.In the literature, citrate toxicity was another important issue, inducing symptoms such as paraesthesia, nausea and vomiting in about 4% of procedures, which is a similar rate to that found here.Other adverse events in our series were mild and did not preclude collection completion in most cases.Only one procedure needed to be interrupted, most likely secondary to a severe infection with sepsis.Overall, authors concluded that ecp collection is safe and well-tolerated in most children.The authors did note that lymphocyte collections decrease haemoglobin, platelet counts and white blood cells.Adverse events are mainly related to vascular access problems, and these events are usually mild but more frequent than in progenitor cell collections.The disposable devices manufactured by terumo bct vietnam, costa rica, lakewood / littleton, co and harmac must have a final sterility assurance level (sal) of < 1.0 x 10-6.This means that following terminal sterilization one or fewer products out of 1 million products sterilized could potentially have a surviving organism.To ensure that this level of sterility is met or exceeded, terumo bct employs a sterility assurance system throughout the entire manufacturing process.The attributes of this sterility assurance system are listed below as well as how each contributes to ensuring the product meets or exceeds the required sal of < 1.0 x 10-6.According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of 4.8%.Adverse effects related to vascular access are a frequent concern.Hematoma, venous sclerosis and thrombosis can complicate percutaneous needle puncture.Hemorrhage or pneumothorax or both may complicate cvc insertion, while thrombosis and infection are the most frequently observed complications of prolonged central venous access.Some of the most common reactions include fever, urticaria, hypocalcemic symptoms, pruritus, dyspnea, tachycardia, and mild hypotension.Transient hypocalcemia associated with apheresis is usually well tolerated.Symptoms often show as parasethesia (tingling) but patients may also experience unusual taste, nausea, lightheadedness, shivering, and tremors.Severe hypocalcemia may also cause muscle contractions and can progress to tetany and seizures if hypocalcemia escalates and is not corrected.As large volumes of donor or patient blood circulate through an apheresis device, blood cells are intentionally or incidentally removed.With current centrifugal technology, reductions in platelet count are usually modest, and levels quickly return to baseline.In a severely thrombocytopenic patient, however, such a loss may mask the beginning of platelet recovery.The small amount of red cells lost in the apheresis circuit may be more apparent in an anemic patient who has meager production capacity and who is receiving multiple procedures.Although generally well tolerated, the large volume leukocytapheresis for stem cell collections in patients often results in a decline in hematocrit and platelet count, particularly because some red cells and platelets are incidentally removed with the stem cells.Since this was a journal publication to assess extracorporeal photopheresis in paediatric patients: a retrospective comparison between different 'off-line' protocols involving 91 patients between september 2006 and november 2019, the lot numbers were not requested; therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.Root cause: based on the available information within the journal article, a definitive root cause could not be determined.The journal mentioned allegations of vascular access issues, hypotension, citate toxicity, drop in hematocrit and platelet loss.The reported hypotension is a common side effect of therapeutic apheresis procedures.It is typically caused by fluid shift, blood loss, length of the procedure, patient's sensitivity to the procedure and/or hemodynamic stress of the procedure.A definitive root cause for the alleged catheter related infection could not be determined, but as stated in the article most catheters were used in the context of transplantation and for longer periods of time than those involved in progenitor cell collection.Prolonged cvl access is known to be a source of bacterial contamination.Possible causes for the alleged citrate reaction include but are not limited to ac management during the procedure, patient disease state, and/or patient sensitivity to anticoagulant.Possible causes for the decrease in rbcs could not be determined but may be related to: *patient¿s low initial hemoglobin prior to apheresis *dilution effects owing to acd-a addition during apheresis *patients¿ underlying disease state *incorrect setting of collection preference resulting in too many rbcs in the collected products cause for the decrease in platelet count could not be determined but it is likely due to one or a combination of the possible causes listed below: *patient's underlying disease state and blood physiology influenced the collected product *inlet flow rate was set too high *running a lengthy procedure cause for the reported hematoma was unable to be determined.Possible causes include but are not limited to: *poor phlebotomy technique causing the needle to unintentionally enter the tissue surrounding the blood vessel *dislodgement of the needle from the vein due to arm movement, a poorly secured needle, or an inadequate choice of venous site to puncture *an excessively high return flow rate article citation: sebastián, e., et.Al.Extracorporeal photopheresis in paediatric patients: a retrospective comparison between different 'off-line' protocols.Vox sang.2022.
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