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This report is being filed to provide additional information in e.1, h.6 and h.10.Investigation: since this was a journal publication presenting data of a prospective study to assess the efficacy and safety of tpe using spectra optia to evaluate the impact of standard-volume pe (svpe) on 21-day transplant-free survival in acute liver failure (alf) patients over a period from january 2016 to september 2018, 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.The authors stated that ¿standard-volume plasma exchange (svpe) using centrifugation technique and response-guided strategy improved overall clinical outcomes.A reduction in the levels of proinflammatory cytokines, damage-associated molecular patterns and amelioration of systemic inflammatory response syndrome was observed with svpe as compared with standard medical treatment.Svpe improved tissue microcirculation and systemic hemodynamics in alf patients by clearing arterial lactate, restoring the balance between plasma adam metalloproteinase with thrombospondin type-1 motif member 13 and von willebrand factor.A lower-volume strategy of plasma exchange (svpe) could effectively improve outcomes in patients with alf by ameliorating systemic inflammation, improving microcirculation, and reducing cerebral edema.Svpe could be routinely recommended for management of non-acetaminophen patients of alf with cerebral edema.¿ according to therapeutic apheresis: a physician's handbook, apheresis procedure itself leads to both hemodynamic and dilutional changes.Those physiologic consequences may also result in adverse events for the patient.Another major category of physiologic responses to therapeutic apheresis is fluid shifts that occur as whole blood is removed, as one or another component is retained, and as the remaining components are returned with or without replacement solution.Resultant changes in intravascular volume can induce hemodynamic alterations.Fluid overload (hypervolemia) may be a problem for patients with cardiac or renal impairment.In other situations, hypovolemia may be a concern.There is general sense that hemodynamic changes are more common with intermittent flow centrifugation than with continuous flow procedures.This situation probably relates to the greater extracorporeal volume associated with earlier models of intermittent flow machines.Therapeutic apheresis procedures may lead to major physiologic changes, including hypocalcemia caused by citrate infusion, hemodynamic changes associated with fluid shifts, and depletion of cellular and plasma constituents.As greater understanding of the physiology of apheresis has guided continued improvements in technology, the potential for untoward effects has been minimized so that procedures may usually be performed without adverse events.According to therapeutic apheresis: a physician's handbook, 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.Similarly, 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.According to the aabb circular of information for the use of human blood components (revised 2017), bacterial sepsis occurs rarely but can cause acute, severe, sometimes life-threatening effects.Onset of high fever (>2 c or > 3.5 f increase in temperature), severe chills, hypotension, or circulatory collapse during or shortly after transfusion should suggest the possibility of bacterial contamination and/or endotoxin reaction in the transfused products.Although platelet components stored at room temperature have been implicated most frequently, previously frozen components thawed by immersion in a water bath and red cell components stored for several weeks at 1 to 6 c have also been implicated.Although most platelet components are controlled for bacterial contamination, this does not completely eliminate the risk.According to the aabb circular of information for the use of human blood components (revised 2017), because whole blood and blood components are made from human blood, they may carry a risk of transmitting infectious agents [eg, viruses, bacteria, parasites, the variant creutizfeldt-jakob disease (vcjd) agent, and, theoretically, the cjd agent].Careful donor selection, available laboratory tests, and pathogen inactivation (when it is utilized) do not totally eliminate these hazards.Also, septic and toxic reactions can result from transfusion of bacterially contaminated blood and blood components.Such complications are infrequent but may be life-threatening.Bacterial sepsis occurs rarely but can cause acute, severe, sometimes life-threatening effects.Onset of high fever (>2 c or > 3.5 f increase in temperature), severe chills, hypotension, or circulatory collapse during or shortly after transfusion should suggest the possibility of bacterial contamination and/or endotoxin reaction in the transfused products.According to therapeutic apheresis: a physician's handbook, metabolism of the citrate anticoagulant consumes hydrogen ions and produces bicarbonate ions.In patients who have renal disease and whose maximal bicarbonate excretion rate is reduced, infusion of citrate often leads to metabolic alkalosis.This state is most often seen with tpe when the replacement fluid is plasma.Alkalosis may make patients more susceptible to adverse consequences of hypocalcemia, and it could slow citrate metabolism.Alkalosis induced by a citrate load from an apheresis procedure will resolve with time or dialysis: in patients for whom alkalosis is a problem, the inlet flow rate into the apheresis machine may be decreased; the amount of citrate may be decreased as well by changing the ratio of anticoagulant to whole blood in the machine.According to the aabb circular of information for the use of human blood and blood components (revised 2017), transfusion-associated circulatory overload (taco) is a frequent complication of transfusion leading to cardiogenic (hydrostatic) pulmonary edema and can occur after transfusion of excessive volumes or at excessively rapid rates.This is a particular risk in individuals with underlying cardiopulmonary or renal disease, the very young and the elderly, and in patients with chronic severe anemia in who low red cells mass is associated with high plasma volume.Small transfusion volumes can precipitate symptoms in at-risk patients who already have a positive fluid balance.Pulmonary edema should promptly and aggressively treated, and infusion of colloid preparations, including plasma components and the supernatant fluid in cellular components, reduced to a minimum.According to the aabb circular of information for the use of human blood components (revised 2017), transfusion-related acute lung injury (trali) is characterized by the acute onset of hypoxemia and noncardiogenic pulmonary edema within 6 hours of a blood or blood component transfusion in the absence of other causes of acute lung injury or circulatory overload.Various stimuli in blood components, most commonly white blood cell (wbc) antibodies from donors sensitized during pregnancy or prior transfusion or transplantation, or proinflammatory molecules that accumulate in stored blood components may cause trali.These mechanisms may not be mutually exclusive and may act synergistically with underlying patient factors to lead to a final common pathway of acute lung injury.These stimuli may trigger an inflammatory response, granulocyte activation and degranulation, and injury to the alveolar capillary membrane and the development of permeability pulmonary edema.Although most trali cases are associated with donor antileukocyte antibodies, rare cases have implicated recipient antileukocyte antibodies that reacted with donor leukocytes.Widespread leukoreduction of blood components has likely mitigated this latter risk.Laboratory testing of blood donors for antileukocyte antibodies or blood components for biological mediators does not alter management of this reaction, which is diagnosed on clinical and radiographic findings.Treatment of trali involves aggressive preferential use of plasma collected from male donors has been associated with a significant reduction in the number of reported trali cases and associated fatalities.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.Root cause: a root cause assessment was performed for the hemodynamic instability.T 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: * patient underlying disease * large volume exchange conducted over a relatively short period treatment.A root cause assessment was performed for the thrombocytopenia.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: * patient's underlying disease state * inlet flow rate was set too high * clumping in the extracorporeal system * running a lengthy procedure * a dilutional effect on the post procedure sample due to the volume of infused acda a root cause assessment was performed for the sepsis.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: * patients' underlying disease diagnosis or comorbidities * complications associated with prolonged use of central venous access.A root cause assessment was performed for the metabolic alkalosis.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: * patients' underlying disease diagnosis * rapid infusion of citrate * use of fresh frozen plasma as replacement fluid a root cause assessment was performed for the transfusion-associated circulatory overload (taco).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: * patients' underlying disease diagnosis or comorbidities * transfusion of excessive volumes or at excessively rapid rates.A definitive root cause of the trali could not be determined.Possible reasons for trali include various stimuli in blood components, most commonly white blood cell (wbc) antibodies from donors sensitized during pregnancy or prior transfusion or transplantation or proinflammatory molecules that accumulate in stored blood components.These mechanisms may not be mutually exclusive and may act synergistically with underlying patient factors to lead to a final common pathway of acute lung injury.These stimuli may trigger an inflammatory response, granulocyte activation and degranulation, and injury to the alveolar capillary membrane and the development of permeability pulmonary edema.Although most trali cases are associated with donor anti-leukocyte antibodies, rare cases have implicated recipient anti-leukocyte antibodies that reacted with donor leukocytes.A root cause assessment was performed for the reported citrate reactions.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.Article citation: maiwall, r.Et.Al.2022.Standard-volume plasma exchange improves outcomes in patients with acute liver failure: a randomized controlled trial.Clinical gastroenterology and hepatology 2022;20:e831¿e854.
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