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Investigation: overview: journal article: hans, et al.: centrifugal therapeutic plasma exchange in pediatric patients.The indian journal of pediatrics (august 2021) 88(8):757¿763 an investigation was conducted for this journal which investigated the safety of therapeutic plasma exchange using cobe spectra, spectra optia, and cs 3000 plus in pediatric populations.A retrospective analysis was performed over a period of 19 years (2001¿2019).There were 672 procedures in 99 pediatric patients.Adverse events occurred in 5% of the procedures (n = 34).The follow adverse events were observed: allergic reaction ((b)(4)%), hypotension ((b)(4)%), symptomatic hypocalcemia ((b)(4)%), line blockage ((b)(4)%), and febrile non hemolytic transfusion reaction ((b)(4)%).A significant correlation of aes was observed with weight, total blood volume of the patient, increasing number of procedures and replacement fluid [fresh frozen plasma (ffp)].All aes were managed as per departmental standard operating procedures (sops) completing procedures successfully except one which was abandoned.No mortality was observed during the procedures.The results are presented in the results section on page 759 and in fig 1 on page 760.However, the authors did not directly link the adverse events to a specific apheresis device.The authors did a retrospective analysis of all tpe procedures performed in children over a period of 19 y (2001¿2019).Tpe procedures were done on three different apheretic devices based on the principle of centrifugation (cs 3000 plus®, fenwal usa, cobe spectra®, terumo bct lakewood, colorado and optia spectra®, terumo bct lakewood, colorado) with extracorporeal blood volume (ecv) as 450 ml, 170 ml, and 141 ml, respectively).Tpe procedures were done on the patients who were not considered for intravenous immunoglobulin (ivig) for neurological conditions like acute inflammatory demyelinating polyradiculoneuropathy (aidp) or for membrane-based apheresis for nephrological indications and thus, were referred to department of transfusion medicine for tpe procedures.Procedures were done daily or on alternate days depending on the clinical condition of the patient.Parameters like height and weight of the patient were noted to calculate the total blood volume of the patient using glicher¿s rule of five [1].Plasma volume of the patient was calculated by considering the hematocrit on the day of the procedure and total blood volume using formulas [3].Patient¿s hemogram, renal function tests, liver function tests, and ionized calcium values were noted before every procedure.Procedure was performed if pre-procedure ionized calcium was = 0.9 mmol/l.For patients having low ionized calcium, correction was requested, which was done by the pediatrician in the ward (1¿2 ml/kg 10% calcium gluconate in 1:1 dilution with normal saline, given slowly over 10¿20 min under cardiac monitoring), ionized calcium was repeated after correction.Informed consent for all the procedures was taken from parents in the presence of the pediatrician.Kit priming for all procedures, the kit was primed with group specific crossmatch compatible non-sagm packed red cells with hematocrit between 65% to 75%.These blood units were used after bringing them to 37 degree celsius using plasmatherm equipment before priming.The volume of prime ranged from 140 to 200 ml (cobe spectra® and optia spectra®, terumo bct lakewood, colorado) and 220 to 400 ml (cs 3000 plus®, fenwal usa).Initially during blood prime, inlet:ac ratio was kept as 50:1which was later changed to 14:1 after connecting the patient.Venous access central venous access was used for inlet as well as return access.Most of the procedures were done using dialysis catheter (8¿9 french) with double lumen at femoral vein.In some procedures internal jugular vein (ijv) central line was also used.Calcium supplementation and monitoring of patient during procedure prophylactic infusion of 1% calcium gluconate was given (prepared by dissolving 10 ml of 10% calcium gluconate in 100 ml normal saline).The rate was adjusted to give total dose of 2 ml/kg over the duration of procedure.The patient was connected to a cardiac monitor throughout the procedure and was monitored by a pediatric and transfusion medicine resident recording the vitals [heart rate (hr), blood pressure (bp), peripheral oxygen saturation (spo2), temperature] every 15 min during the procedure.In patients on inotropes, drug dose adjustment during procedure was done by pediatric resident.Rinse back was omitted as the circuit was primed with packed red blood cells (prbcs).Any adverse event occurring during procedure was noted and analyzed as procedure related, replacement fluid related and vascular access related and graded as mild, moderate and severe depending on the symptoms and management required as per common terminology criteria for adverse events (ctcae) terminology [4].Results the authors performed a total of 672 therapeutic plasma exchange procedures in 99 pediatric patients (11% referred from icu) over a period of 19 y with a mean age of the patient as 7.0 ± 3.11 y.Male to female ratio was 2.3 : 1.The demographic details of the patients are shown in table 1.Tpe was done for various indications in the authors patients like hematological (n = 68), renal (n = 12), neurology (n = 18), and hepatology (n = 1).The most common diagnosis for the procedure in the present study was atypical hemolytic uremic syndrome (63.6%).Other diagnoses are shown in table 2 as per their asfa category.Inlet flow rate for tpe procedure ranged from 6.0 to 23.6 ml/min with a mean flow of 16.45 ± 4.82 ml/min.Timings for procedure ranged from 74 to 172 min.Out of a total of 672 procedures, adverse events were observed in 34 procedures ((b)(4)%).The most common adverse event was replacement fluid¿related [allergic reaction presenting as urticaria, rash and itching in (b)(4)% procedures and febrile non hemolytic transfusion reaction (fnhtr) in (b)(4)%] followed by procedure-related complication namely hypotension (1.04%) and symptomatic hypocalcemia presenting as pain abdomen, nausea, and vomiting in 1.04% of procedures done.Venous access-related complications (intravenous-line blockage) was observed in (b)(4)% of procedures as shown in fig.1.Replacement fluid used was fresh frozen plasma (ffp) in (b)(4)% patients and human serum albumin (hsa) in (b)(4)% patients.All adverse events were of grade 3 severity, which were managed as per departmental standard operating procedures (sops) and procedures were completed successfully except in one where patient developed bradycardia (hr < 45 beats/min) after replacing 50% of his plasma volume with 0.9% normal saline and 5% human serum albumin in ratio of 70 : 30.The procedure was terminated, patient was resuscitated, recovered, and shifted back to intensive care unit (icu).The procedure was going on cs 3000 plus after manual priming with prbc.No mortality was observed during the procedures.The authors also tried to find out the correlation between physical parameters of the patient and procedural parameters with the rate of adverse events and found that there was no statistically significant correlation of adverse events with age, sex, type of apheretic device used for procedure, and different indications for plasma exchange however significant correlation was found with weight (p = 0.045) and total blood volume of the patient (p = 0.04).Also, the rate of adverse events was significantly correlated with increasing number of procedures (p = 0.000) and replacement fluid (ffp) (p = 0.04) as shown in table 3.Another challenge faced in these patients was maintaining adequate access flow rates due to their poor venous caliber.The large bore needle of 16 gauge integrated to the disposable tpe kits is not suitable for venipuncture in the pediatric population.So, central lines are always preferred in these patients to have a continuous flow for maintaining the interface for different cellular and noncellular components of the blood.However, these may get thrombosed or infected which can affect the procedure schedule.The commonest adverse events were related to venous access (50% patients) followed by symptomatic hypocalcemia whereas in the present study, the authors observed symptomatic hypocalcemia in 1.04% procedures and adverse events related to venous access as 0.59% only.The authors used ffp as replacement fluid in their patients with thrombotic microangiopathy as per the recommendations of asfa guidelines [2]; hence, majority of adverse events in the patient were related to the type of replacement fluid with statistically significant correlation.The commonest adverse reaction observed in the present study was mild allergic reactions to plasma proteins of ffp and is similar to findings by sinha et al.[11] and jukic et al.[7] who observed adverse events in (b)(4)% of procedures where ffp was used as replacement fluid as compared to (b)(4)% with albumin.The authors also observed a significant correlation of rate of adverse event with the number of procedures and since most of the patients were of thrombotic microangiopathy and underwent more than 5 procedures, so the adverse events were higher in these patients ((b)(4) total adverse events) as compared to other diagnoses.Conclusion tpe using apheretic devices based on centrifugation is a safe therapeutic modality in children when performed with adequate precautions and under expert technical supervision with proper sops in place.Since this is a retrospective study which evaluated the safety of therapeutic plasma exchange in pediatric populations over a period of 19 years (2001¿2019), the lot numbers were not provided; therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.Adverse events occurred in 5% of the procedures (n = 34).The follow adverse events were observed: allergic reaction (2.24%), hypotension ((b)(4)%), symptomatic hypocalcemia ((b)(4)%), line blockage ((b)(4)%), and febrile non hemolytic transfusion reaction (0.41%).According to the aabb circular of information for the use of human blood components (revised 2017), allergic reactions frequently occur (ie, 1-3% of plasma-containing components) as mild or self-limiting urticaria or wheezing that usually respond to antihistamines.More severe manifestations, including respiratory and cardiovascular symptoms, are more consistent with anaphylactoid/anaphylactic reactions and may require more aggressive therapy (see below).No laboratory procedures are available to predict these reactions.Anaphylactic reactions, characterized by hypotension, tachycardia, nausea, vomiting and/or diarrhea, abdominal pain, severe dyspnea, pulmonary and/or laryngeal edema, and bronchospasm and/or laryngospasm, are rare (<10/100,000 transfused units) but dangerous complications requiring immediate treatment with epinephrine.While these reactions have been reported in iga-deficient patients with anti-iga antibodies and patients with haptoglobin deficiency, most reactions are idiosyncratic and not associated with a specific serum protein deficiency, polymorphism, or identifiable cause (see attachment, 2017 aabb circular page 6 in content tab).According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of (b)(4)%.Some of the most common reactions include fever, urticaria, hypocalcemic symptoms, pruritus, dyspnea, tachycardia, and mild hypotension (see attachment, therapeutic apheresis: a physician's handbook, pgs 28-33).According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of 4.8%.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 paresthesia (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 (see attachment, therapeutic apheresis: a physician's handbook, pgs 28-33).According to therapeutic apheresis: a physician's handbook, adverse effects related to vascular access are a frequent concern.Hemorrhage or pneumothorax or both may complicate cvc insertion, while thrombosis and infection are the most frequently observed complications of prolonged central venous access.During a dressing change, the site should be cleaned and observed for signs of infection such as redness, swelling, drainage, and foul odor.If an infection is suspected, cvc removal should be considered, and the patient should be treated for infection as appropriate.The cause of a cvc flow problem may sometimes be difficult to determine, although patient repositioning will sometimes improve flow.A common situation is that the cvc can be flushed without resistance but does not yield blood return; this scenario may be the result of kinking, poor positioning, intralumenal clots, or venous thrombosis.Blocked cvcs can sometimes be cleared with a fibrinolytic agent such as tpa.The placement of a cvc is considered by some to be the greatest risk related to the apheresis procedures, and it should be avoided if the procedure can be performed using peripheral iv (see attachment, therapeutic apheresis: a physician's handbook, pgs 32-33).According to the aabb circular of information for the use of human blood components (revised 2017), febrile nonhemolytic reactions are typically manifested by a temperature elevation of >1c or 2f occurring during or within 4 hours after a transfusion and in the absence of any other pyrexic stimulus or active warming.Febrile reactions may occur in less than 1% of transfusion of leukocyte-reduced red cell components and about 5% of leukocyte-reduced apheresis platelet components.Febrile reactions occur more frequently in patients receiving non-leukocyte-reduced components and those previously alloimunized by transfusion or pregnancy.Antipyretics usually provide effective symptomatic relief.Patients who experience repeated, severe febrile reactions may benefit from receiving leukocyte-reduced components.If these reactions are caused by cytokines in the component, prestorage leukocyte reduction may be beneficial root cause: a root cause assessment was performed for the allergic reaction.The reported adverse events are common side effects of transfusion and apheresis procedures.The authors stated that "mild allergic reactions to plasma proteins in fresh frozen plasma".A root cause assessment was performed for the hypotension.Based on the available information a definitive root cause could not be determined.Hypotension is a common side effect of therapeutic apheresis procedures.They are typically caused by the patient's disease state, the blood loss, the length of the procedure, the patient's sensitivity to the procedure and/or the hemodynamic stress of the procedure.A definitive root cause for the reported citrate reactions could not be determined.These reactions occur due to decreased ionized calcium in circulation as a result of exogenous citrate administered during the apheresis procedure and are influenced by patient physiology, the patient's disease state, the rate of ac infusion, the citrate contents in the replacement fluid, and/or the length of the procedure.These symptoms may be treated with oral or intravenous calcium supplements or by adjusting the ac infusion rate.A root cause assessment was performed for the line blockage.Based on the available information a definitive root cause could not be determined but it is likely due to one or a combination of the possible causes listed below: poor maintenance of the catheter.Hypercoagulopathy associated with the patient's underlying disease state.A root cause assessment was performed for the febrile non-hemolytic transfusion reaction.The reported adverse events are common side effects of transfusion.Based on the available information a definitive root cause could not be determined but it is likely due to one or a combination of the possible causes listed below: the action of antibodies against white cells or the action of cytokines either present in the transfused component or generated by the recipient in response to transfused elements.Patients received non-leukocyte-reduced components.Patients were previously alloimunized by transfusion or pregnancy.Article citation: hans et al 2021.Centrifugal therapeutic plasma exchange in pediatric patients.The indian journal of pediatrics (august 2021) 88(8):757¿763.Https://doi.Org/10.1007/s12098-020-03657-6.
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