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Plasma exchange in the intensive care unit: A 10 year retrospective audit Emily Paton RN, Grad. Dip (Crit Care Nurs), ACCCN ∗ , Ian C. Baldwin RN, PhD, (ICU Cert), ACCCN 1 Department of Intensive Care, Austin Health, 145 Studley Rd, Heidelberg, Melbourne 3084, Australia
article information Article history: Received 10 April 2013 Received in revised form 23 September 2013 Accepted 3 October 2013 Available online xxx Keywords: Intensive Care Unit Plasma exchange Plasmapheresis Retrospective audit ICU protocol and guidelines
a b s t r a c t Background and aims: Plasma exchange (PE) is a therapeutic technique for the removal of illnessassociated antibodies and toxins. Little is currently known about the prescription and technique for PE in the Intensive Care setting. In addition, different illnesses require specific PE regimens to optimise the clinical outcome for the patient. We sought to audit our use of PE for: number of treatments, clinical indications, treatments prescribed and administered, any procedural or patient complications, and adherence to current best practice recommendations. Method: A retrospective audit involving all patients who were admitted to our tertiary 20 bed Intensive Care Unit (ICU) and received PE therapy between 1 January 2002 and 31 December 2011. Data was collected from identified patient medical records using a specifically designed case report form. Results: Thirty unique patients were identified in this audit. There was an incidence of 0.15% use of PE during this period. Eighteen female patients (60%) were indentified, median age 59.5 (48–70) years. These 30 patients were prescribed 135 PE treatments, requiring 156 membranes in total with a 15.5% incidence of premature circuit clotting. Thrombotic Thrombocytopenic Purpura (TTP) was the most common indication for PE (37%) with 10 other clinical indications. Median length of ICU admission was 9.5 (3–17) days. The PE regimens received by patients in this ICU were not always prescribed in accordance with current best practice recommendations. No patient complications were identified with these PE treatments. Conclusion: PE is a valuable treatment option for critically ill patients suffering antibody-mediated illness. The findings of this audit have identified differences between the current prescription recommendations for PE and those applied. TTP was the most common indication for PE, and no patient complications were identified, however a 15.5% incidence of circuit clotting occurred. The infrequency of the therapy and the different indications present a challenge for Intensive Care clinicians to provide best care in all cases. Improving the prescription of PE through the implementation of a new protocol and clinical education may result in better outcomes for our patients. © 2013 Australian College of Critical Care Nurses Ltd. Published by Elsevier Australia (a division of Reed International Books Australia Pty Ltd). All rights reserved.
Background Plasma exchange (PE) is a therapeutic intervention offered to patients suffering antibody-mediated illnesses and protein bound metabolite toxicities. This procedure is also known as therapeutic plasma exchange (TPE) or plasmapheresis and can be performed in the Outpatients Department or Intensive Care setting. The aim of PE is to remove toxins held within the patient’s plasma.1,2 These toxins are unique to specific disease processes, however they must be of large molecular size to warrant PE therapy.1,3 Some of
∗ Corresponding author. E-mail addresses: [email protected] (E. Paton), [email protected] (I.C. Baldwin). 1 Fax: +61 3 9496 3932.
the pathogenic substances for removal include: immunoglobulins, antibodies, and toxic plasma proteins.1,2 These large substances are often resistant to excretion by the body’s normal endogenous clearance pathways and other haemodialysis techniques. This process was first described in the early 19th century using animal experimentation models.1 In the 1950s, it was applied to humans with the initial purpose of harvesting plasma. This blood purification technique was then utilised for illnesses such as Waldenström’s Macroglobulinemia (WM), Goodpasture’s Syndrome, and Thrombotic Thrombocytopenic Purpura (TTP) in the 1960–1970s.1 Over time the use of PE has continued to develop as an effective treatment option for these antibody-mediated illnesses. In our Intensive Care Unit (ICU) a single machine can be used interchangeably between continuous renal replacement therapy (CRRT) and PE. The membrane used for PE is different to CRRT and
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http://dx.doi.org/10.1016/j.aucc.2013.10.001
Please cite this article in press as: Paton E, Baldwin IC. Plasma exchange in the intensive care unit: A 10 year retrospective audit. Aust Crit Care (2013), http://dx.doi.org/10.1016/j.aucc.2013.10.001
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allows for the larger plasma molecules to be removed. In our ICU a brief protocol has been established for PE with use over 20 years. However there is no dedicated database to fully understand the number of patients treated annually, treatment techniques used, adverse effects and outcomes. In this retrospective audit we report a 10 year experience with PE and review how the implementation of PE compares with the current best practice recommendations published in 2010 by the American Society for Apheresis (ASFA).4 These expert consensus guidelines are the Fifth Edition from the ASFA and represent expertise from 10 centres in North America. These guidelines contain graded levels of evidence for the use of PE including specific prescription details (indications, frequency, replacement volume and fluid, treatment durations) however they are not specific to the ICU.4 Methods We undertook a single centre retrospective audit in our metropolitan tertiary ICU comprising critically ill medical, and surgical, adult patients. This 20 bed ICU provides specialised services for cardiac and major vascular surgery, liver failure and transplantation, acute spinal injuries, and specialises in acute renal failure support systems. This audit reviewed the full medical records of patients who received PE therapy in the ICU between 1 January 2002 and 31 December 2011. Eligible patients were identified using a computerised search of the password protected Australasian Outcomes Research Tool for Intensive Care (AORTIC software V 9.2.3, Metafacts PTY LTD, Sydney, Australia) database, using the key term ‘plasma exchange’.5 No exclusions were applied. Therefore our key aims were to review and critique our use of PE for: the incidence, clinical indications, treatments prescribed and administered, any procedural or patient complications, and adherence to current best practice recommendations. Data was collected from the identified patient records using a purpose designed case report form. Patient demographic data sourced included: age, gender, admission diagnosis, acute physiology and chronic health evaluation (APACHE) III score, length of ICU and hospital stay. The procedural data collected for each patient included: indication for implementation, treatment duration, type and amount of replacement fluids, incidence of clotting, and any procedural or patient complications. Outcome data for survival and discharge location was also determined. Documents reviewed for data collection in this audit included: daily progress notes and discharge summary, ICU observation charts, drug and therapy orders, ICU medical round notes, and intravenous therapy order forms. One researcher collected and de-identified all data and referred to a senior researcher when clarification was required to manage any difficulties interpreting the clinical documentation.
Fig. 1. Number of patients receiving PE 2002–2011.
in the annual use of PE over the 10 years, as represented in Fig. 1. Demographic data for these patients is presented in Table 1. The median age of patients was 59.5 (48–70) years, of which there were 18 females. Median length of ICU admission was 9.5 (3–17) days. The median APACHE III score for patients in the audit was 62.5 (55–84), which is consistent with critical illness managed in a tertiary ICU.6 PE was indicated for multiple different diseases, with TTP associated illness being the most common (11 patients). The frequency of all presentations is further illustrated in Fig. 2. Plasma exchange procedure During this 10 year period, 135 PE procedures were completed. The median number of treatments per patient per ICU admission was four (2–5). The timeframe for treatment duration varied, however the most common was 6 h (62 treatments), followed by a 4 h duration used in 21 treatments. Some of the treatment durations were unable to be found in patient medical records due to data not being recorded. Of the 135 PE treatments analysed in this audit, 103 (76%) where prescribed at a 3 L exchange volume (range 1–5 L). In addition, this audit found the most commonly used replacement fluid was fresh frozen plasma (FFP) in 40 treatments. This may be in association with the high incidence of TTP, which was managed with fresh frozen plasma as the predominant replacement fluid. The next most common treatment regimen, used in 26 treatments, was 50% fresh frozen plasma and 50% human albumin 4%. Other common regimens included mixtures of 66.6% FFP and 33.3% human albumin 4% in 19 treatments, and mixtures of 33.3% FFP and 66.6% human albumin 4% in 18 treatments. Overall,
Data analysis Statistical analysis was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC). Category variables would be expressed as frequency or number and percentage (%), and continuous variables that are normally distributed using mean ± standard deviation (±SD). When data was not normally distributed, median with 25th and 75th interquartile range (IQR) was used. Results The audit identified 30 patients who received PE in the ICU over the 10 year period. Total ICU admissions for this period were 19,728 resulting in a 0.15% incidence for the use of PE. There was no trend
Fig. 2. Indications for PE: illness & frequency.
Please cite this article in press as: Paton E, Baldwin IC. Plasma exchange in the intensive care unit: A 10 year retrospective audit. Aust Crit Care (2013), http://dx.doi.org/10.1016/j.aucc.2013.10.001
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Table 1 Demographic data for the 30 patients where PE was prescribed. Reason for ICU admission
Gender M/F
Age
APACHE III
Medical Emergency Team (MET) call – ongoing seizures Post liver transplant Hypercapnic respiratory failure – requiring intubation MET call/CODE BLUE – respiratory distress – requiring intubation Guillain-Barré Syndrome (GBS) – requiring respiratory support Thrombotic Thrombocytopenic Pupura (TTP) – requiring plasma exchange Respiratory failure MET call – exacerbation of Myasthenia Gravis (MG) MET call – respiratory distress Hypoxia Transfer from another hospital – septic shock TTP – requiring plasma exchange MET call–hypoxia Transfer from another hospital – respiratory failure – history of MG Possible TTP Post liver transplant Altered conscious state MET call – status epilepticus – requiring intubation ICU review – increased malena, decreased haemoglobin despite transfusions Status epilepticus Transfer from another hospital – severe anaemia – for plasma exchange Pancreatitis Relapsed TTP – for plasma exchange MET call – respiratory failure TTP Post coronary artery bypass grafts ×5 Post liver and kidney transplant Post mitral valve replacement redo Fulminant liver failure Erythropoetic protporphyria–pre liver transplant
F F F M F M F F F M M M F F F F F F M F M M M M F M F F M F
66 42 78 54 71 57 77 60 64 68 44 43 79 68 45 62 75 59 64 23 49 48 47 70 51 75 54 71 59 22
61 52 52 59 60 132 63 50 61 68 123 41 97 84 39 57 88 62 73 55 71 98 38 93 37 86 61 72 66 65
Number (/) or median value and (25–75th) IQR
12/18
59.5 (48–70)
a combination of different replacement fluids was the preferred prescription regimen as identified in 91 (67%) PE treatments. This may be attributed to prescribing doctors aiming to imitate normal plasma constituents as much as possible in the replacement fluid. The remaining exchanges were prescribed with a single replacement fluid; FFP in 40 regimens, and human albumin 4% in the remaining four. Technical aspects of PE treatment This audit showed that more than one plasma membrane was required to complete some treatments. This was a result of blood clot formation in the extracorporeal circuit. For the 135 ordered PE treatments, 156 PE membranes were used to complete the prescribed therapy. Early cessation of PE therapy due to coagulation in the extracorporeal circuit occurred 21 times (15.5%) which resulted in a new circuit being primed to complete the PE therapy. Vascular access was also a complication that disrupted the PE procedure. In some instances the access catheter required replacement before PE therapy could be recommenced, resulting in treatment delay. The use of anticoagulation therapy during PE treatments was poorly documented. Therefore, if no documentation was found it was assumed that no anticoagulation was administered. Of the 156 PE treatments, 52 records showed that heparin was given for 10 different patients receiving PE therapy. Another two patients were receiving Dextran 40 (an antithrombotic) at the time of PE. Furthermore, of the 21 membranes that clotted there were six incidences where the patient was already receiving heparin. Discussion We report data from an audit of PE use in our ICU over 10 years. There were 11 different indications in the identified 30 patients
62.5 (55–84)
Length of stay ICU
Hospital
10 2 9 15 44 6 17 4 4 10 19 2 7 11 4 2 10 3 2 25 9 20 3 23 1 17 10 17 13 2
43 24 102 62 152 44 44 73 22 33 76 32 45 22 12 26 18 37 27 74 10 24 6 27 15 17 86 29 33 10
9.5 (3–17)
30.5 (22–45)
for the use of PE, with TTP being the indication in 37%. Only one other similar report was identified in the literature, also in a single centre over 10 years, reflecting a much higher use of PE with 330 patients and 1188 PE treatments. A key finding of this retrospective clinical study was the use of PE to manage sepsis; 46% of patients.7 A severity of illness score was not provided, however an overall mortality rate of 54.1% was reported.7 In our study, the median APACHE III score was 62.5 indicating a medium level of illness severity.8 Of the 30 patients six died in ICU; a 20% ICU mortality rate.
Thrombotic Thrombocytopenic Purpura Thrombotic Thrombocytopenic Purpura (TTP) was the most common indication for PE therapy. Eleven patients were suspected to have TTP. Five patients received FFP as sole the replacement fluid, which is in concurrence with the current best practice ASFA guidelines.4 The remaining six patients received a combination of FFP and human albumin 4%. The most common treatment time was 6 h. There is no recommended duration of treatment identified in the literature. Patients with TTP in this audit received a 3–4 L volume exchange which is approximately one plasma volume, depending on the patient’s weight which is in accordance with current recommendations.1,4,9,10 The results of this audit show that the recommended volume of PE was administered however, the type of fluid used for each treatment was not always consistent with current best practice recommendations.4,9,11 This audit was not focused to identify improvements in the patient’s symptoms following PE therapy. However, eight of the patients admitted for the management of TTP were discharged from hospital. The remaining three patients did not survive their ICU admission.
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Peripheral neurological disorders
ABO incompatible organ transplantation
This audit identified five patients with peripheral neurological disorders. Three patients required PE for the treatment of Myasthenia Gravis (MG), and two for the management of Guillain-Barré Syndrome (GBS). Both patients with GBS were treated with two cycles of PE therapy, each cycle consisted of consecutive daily PE treatments over either four or five days. All of the 18 PE treatments involved a 3 L exchange using a mixture of FFP and human albumin 4%, which was administered over a 3–6 h period. This identifies that some treatments did not follow current best practice recommendations which suggest the implementation of 5–6 s daily PE treatments with human albumin 4% as the sole replacement fluid.4,12,13 The three patients that required PE for the management of MG were administered 3 L or 5 L exchanges with a mixture of FFP and human albumin 4% or human albumin 4% alone over a 6–14 h period. PE was administered daily with FFP frequently used as a portion of the replacement fluid. Current best practice guidelines recommend the use of daily or second daily PE therapy with human albumin 4% as the sole replacement fluid for management of patients with MG.4,14–17 This identifies a difference between clinical practice and the literature reviewed which may need to be taken into consideration for future patients. Compliance to current ASFA recommendations could be improved with the implementation of an updated plasma exchange protocol in our ICU.
Four patients were identified by this audit to have received PE post organ transplantation and one patient pre organ transplantation. The two patients that received PE post organ transplantation required only one treatment, the exchanges were either FFP and human albumin 4% or FFP alone. Both of these patients received a 3 L PE regimen over 6 h. The other two patients that received PE post organ transplantation required four or five PE treatments which exchanged 1–4 L of plasma with either FFP alone or FFP and human albumin 4% over a 1–6 h timeframe. The patient that received PE pre organ transplantation was administered one treatment to remove 3 L of plasma, replaced with human albumin 4% over a 4 h period. The current best practice recommendations suggest PE regimens with albumin 4% as the sole replacement fluid unless severe coagulopathy is present.4,22,23 Of these five patients that received PE related to organ transplantation, four patients were discharged home and one was transferred to another hospital.
Renal disorders The category of renal disorders incorporates multiple different illnesses including; Waldenström’s Macroglobulinemia (WM), Anti-Neutrophil Cyroplasmic Antibody (ANCA), and antiglomerular basement membrane disease (anti-GBM). One patient was admitted to the ICU with suspected WM. This patient received three 4 L PE treatments which were replaced with varying combinations of human albumin 4%, FFP and plasmalyte over a 6 h timeframe. The current guidelines for the management of WM recommend human albumin 4% as the primary replacement fluid.4,18 Therefore the PE regimen was not in accordance with current best practice guidelines for patients with WM.4,18,19 This patient died in the ICU, however other aspects of the patient’s condition were not the focus of this audit such that PE should not be considered an ineffective treatment option for patients with WM. Two patients in this audit presented to the ICU with ANCA and received daily PE for five and seven days. Both these patients were prescribed a regimen of 3 L FFP or a mixture of FFP and human albumin 4% over a 3–6 h period. The ASFA recommend the use of albumin 4% in patients with ANCA, therefore this aspect of the treatment regimen was not in accordance with the current best practice ASFA guidelines.4 In addition, three patients required PE therapy for the treatment of anti-GBM disease. One patient was administered PE that failed to complete due to clotting in the extracorporeal circuit and was not recommenced. This patient also died in the ICU indicating that there may have been other clinical factors affecting their outcome. The other two patients with anit-GBM disease received daily PE treatments for 4 or 16 days. The regimen implemented for these two patients utilised a 3 L exchange that was replaced with a mixture of FFP and human albumin 4% over 6 h. The administered exchange volume and frequency for these two patients was in accordance with current best practice recommendations, however the recommended replacement fluid is albumin 4% which was not the sole replacement fluid administered for these two patients.4,20,21 One of these patients was discharged home and the other discharged to a rehabilitation facility.
Summary of discussion This 10 year retrospective audit has provided insight into the use of PE therapy in our ICU. Inconsistency in the prescription of PE therapy between patients and within a single patient implies that current best practice recommendations were not the influencing factor for prescribing PE. This indicates that either uncertainty and or past clinician experience may be the underlying reason for the choice of the PE regimen rather than reference to current best practice guidelines. The majority of patients reviewed in this study were discharged home or to a rehabilitation facility. Large cohort studies comparing different techniques for PE are difficult to implement in a single centre due to the rarity of the illnesses requiring PE therapy. Therefore, future studies would benefit from being multicentre to enable greater patient numbers, which would allow for a more robust study powered to test a comparative study hypothesis with conclusions for best practice accordingly. Following our audit and review of the literature, we recommend 1. Implement a simple, succinct prescribing document. Table 2 provides suitable information for prescribing and implementing PE in the ICU with evidence cited accordingly. This will assist doctors and nurses to ensure the regimen is correctly prescribed, implemented and well recorded in patient medical records. 2. Ensure the PE current best practice guidelines4 and hospital protocol are in an accessible location for all staff (paper or electronic). 3. Provide areas for documentation of anticoagulation and any adverse events during PE in ICU charts or electronic notes. 4. Higher doses of anticoagulation may reduce clotting during PE. This will reduce costs and nursing time where two membranes and circuits are needed to complete one treatment. Heparin or any drug used will be cleared at a higher rate with both watersoluble and protein bound losses occurring during PE. 5. Avoid delays on commencing PE in critically ill patients. PE appears to be a safe and well tolerated treatment in the ICU. Limitations This audit was limited by the small number of patients identified, and the retrospective nature of the study. All treatments were critiqued against current best practice recommendations which may have influenced our findings. Documentation of the PE regimen was not easily found and was often split over multiple different hospital medical records and charts in the ICU. Complications reported were not pre defined and this may have influenced our
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Table 2 Information for prescribing and implementing PE in the ICU. Disease or illness
Substance for removal
Thrombotic Thrombocytopenic Purpura (TTP)
Antibodies that inhibit ADAMTS13
Guillain-Barré Syndrome (GBS)
Antibodies
Myasthenia Gravis (MG) NB 2nd line or treatment in a crisis
Acetylcholine receptor (AChR) antibodies
Waldenström’s Macroglobulinemia (WM)
Immunoglobulin (IgM)
Anti-glomerular basement membrane (anti-GBM) disease Overdose or poisoning
Anti-GBM antibodies
Protein bound toxins
ABO incompatible (ABOi) transplant
Anti-A and/or Anti-B antibodies
Rationale
Suggested regimen
A deficiency of ADAMTS13 enzyme is a result of auto-antibodies24,25 Prompt commencement is most effective4,12 PE is fast acting (days) with a short duration of action (weeks).16 Most beneficial in a myasthenic crisis or as a bridging tool16 Increased IgM creates hyperviscosity.18 A single PV exchange will reduce circulating IgM by 50–60%1 PE therapy removes anti-GBM antibodies therefore reversing the effect of the disease21 PE therapy removes highly protein bound toxins, but limited by unique characteristics of toxins4 PE therapy can reverse the clinical and pathologic manifestations of rejection4,23
Fluid
Amounta
Frequency
FFP4,9,11
4–6 L 1–1.5 PV4,9,10
Daily or twice daily4,9,10
Albumin1,4,12
4–6 L 1–1.5 PV4,13 4–6 L 1–1.5 PV4,15–17
2nd daily4
Albumin1,4,18
4–6 L 1–1.5 PV1,4,18
Daily4
Albumin4,11,21
4–6 L 1–1.5 PV4
Daily4,11,21
Albumin4
4–8 L 1–2 PV4
Daily4
Albumin22,23
4–6 L 1–1.5 PV4,22,23
2nd daily pre transplant22,23 daily or 2nd daily post transplant4
Albumin4,14
2nd daily15–17
PV, plasma volumes; FFP, fresh frozen plasma (containing ADAMTS13 enzymes); CNS, central nervous system. a Volumes are given based on an 80 kg person (one plasma volume = 50 ml/kg).
findings for this study aim. To allow for adequate data to be collected, assumptions were made from the partial documentation on the multiple documents within the patients’ medical files to establish specific parts of the implemented PE regimen.
Conflicts of interest None to declare. Authors’ contributions
Strengths This audit for the use of PE in our ICU has not been previously done. This audit gives insight into our ICU with PE therapy over a 10 year period where data and adherence to clinical recommendations in the literature is lacking. We provide clinical recommendations to improve the use of PE in our ICU and others. This may also contribute to improvement in patient outcomes if PE therapy is implemented in accordance with these recommendations. Conclusion Plasma exchange is an infrequent procedure in the ICU. TTP was the most common clinical indication for PE. Coagulation in the extracorporeal circuit resulting in broken treatment procedures is a clinical challenge in providing PE, however our audit suggests it is a safe treatment for critically ill patients when required. This audit also supports the rationale for early commencement of treatment before test results have confirmed the nature of the illness, as the risks associated with PE therapy appear to be less than those associated with the potential delay in treatment in many patients. As prescribing recommendations were not always followed, the implementation of a succinct documentation and prescription protocol for PE would ensure that current best practice recommendations are easily accessible and may improve outcomes for PE in the ICU. Ethical approval This study was approved as an audit activity by the Austin Health Office for Research. The HREC approval number is H2012/04795.
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Contents lists available at ScienceDirect
Australian Critical Care journal homepage: www.elsevier.com/locate/aucc
Plasma exchange in the intensive care unit: A 10 year retrospective audit Emily Paton RN, Grad. Dip (Crit Care Nurs), ACCCN ∗ , Ian C. Baldwin RN, PhD, (ICU Cert), ACCCN 1 Department of Intensive Care, Austin Health, 145 Studley Rd, Heidelberg, Melbourne 3084, Australia
article information Article history: Received 10 April 2013 Received in revised form 23 September 2013 Accepted 3 October 2013 Available online xxx Keywords: Intensive Care Unit Plasma exchange Plasmapheresis Retrospective audit ICU protocol and guidelines
a b s t r a c t Background and aims: Plasma exchange (PE) is a therapeutic technique for the removal of illnessassociated antibodies and toxins. Little is currently known about the prescription and technique for PE in the Intensive Care setting. In addition, different illnesses require specific PE regimens to optimise the clinical outcome for the patient. We sought to audit our use of PE for: number of treatments, clinical indications, treatments prescribed and administered, any procedural or patient complications, and adherence to current best practice recommendations. Method: A retrospective audit involving all patients who were admitted to our tertiary 20 bed Intensive Care Unit (ICU) and received PE therapy between 1 January 2002 and 31 December 2011. Data was collected from identified patient medical records using a specifically designed case report form. Results: Thirty unique patients were identified in this audit. There was an incidence of 0.15% use of PE during this period. Eighteen female patients (60%) were indentified, median age 59.5 (48–70) years. These 30 patients were prescribed 135 PE treatments, requiring 156 membranes in total with a 15.5% incidence of premature circuit clotting. Thrombotic Thrombocytopenic Purpura (TTP) was the most common indication for PE (37%) with 10 other clinical indications. Median length of ICU admission was 9.5 (3–17) days. The PE regimens received by patients in this ICU were not always prescribed in accordance with current best practice recommendations. No patient complications were identified with these PE treatments. Conclusion: PE is a valuable treatment option for critically ill patients suffering antibody-mediated illness. The findings of this audit have identified differences between the current prescription recommendations for PE and those applied. TTP was the most common indication for PE, and no patient complications were identified, however a 15.5% incidence of circuit clotting occurred. The infrequency of the therapy and the different indications present a challenge for Intensive Care clinicians to provide best care in all cases. Improving the prescription of PE through the implementation of a new protocol and clinical education may result in better outcomes for our patients. © 2013 Australian College of Critical Care Nurses Ltd. Published by Elsevier Australia (a division of Reed International Books Australia Pty Ltd). All rights reserved.
Background Plasma exchange (PE) is a therapeutic intervention offered to patients suffering antibody-mediated illnesses and protein bound metabolite toxicities. This procedure is also known as therapeutic plasma exchange (TPE) or plasmapheresis and can be performed in the Outpatients Department or Intensive Care setting. The aim of PE is to remove toxins held within the patient’s plasma.1,2 These toxins are unique to specific disease processes, however they must be of large molecular size to warrant PE therapy.1,3 Some of
∗ Corresponding author. E-mail addresses: [email protected] (E. Paton), [email protected] (I.C. Baldwin). 1 Fax: +61 3 9496 3932.
the pathogenic substances for removal include: immunoglobulins, antibodies, and toxic plasma proteins.1,2 These large substances are often resistant to excretion by the body’s normal endogenous clearance pathways and other haemodialysis techniques. This process was first described in the early 19th century using animal experimentation models.1 In the 1950s, it was applied to humans with the initial purpose of harvesting plasma. This blood purification technique was then utilised for illnesses such as Waldenström’s Macroglobulinemia (WM), Goodpasture’s Syndrome, and Thrombotic Thrombocytopenic Purpura (TTP) in the 1960–1970s.1 Over time the use of PE has continued to develop as an effective treatment option for these antibody-mediated illnesses. In our Intensive Care Unit (ICU) a single machine can be used interchangeably between continuous renal replacement therapy (CRRT) and PE. The membrane used for PE is different to CRRT and
1036-7314/$ – see front matter © 2013 Australian College of Critical Care Nurses Ltd. Published by Elsevier Australia (a division of Reed International Books Australia Pty Ltd). All rights reserved.
http://dx.doi.org/10.1016/j.aucc.2013.10.001
Please cite this article in press as: Paton E, Baldwin IC. Plasma exchange in the intensive care unit: A 10 year retrospective audit. Aust Crit Care (2013), http://dx.doi.org/10.1016/j.aucc.2013.10.001
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allows for the larger plasma molecules to be removed. In our ICU a brief protocol has been established for PE with use over 20 years. However there is no dedicated database to fully understand the number of patients treated annually, treatment techniques used, adverse effects and outcomes. In this retrospective audit we report a 10 year experience with PE and review how the implementation of PE compares with the current best practice recommendations published in 2010 by the American Society for Apheresis (ASFA).4 These expert consensus guidelines are the Fifth Edition from the ASFA and represent expertise from 10 centres in North America. These guidelines contain graded levels of evidence for the use of PE including specific prescription details (indications, frequency, replacement volume and fluid, treatment durations) however they are not specific to the ICU.4 Methods We undertook a single centre retrospective audit in our metropolitan tertiary ICU comprising critically ill medical, and surgical, adult patients. This 20 bed ICU provides specialised services for cardiac and major vascular surgery, liver failure and transplantation, acute spinal injuries, and specialises in acute renal failure support systems. This audit reviewed the full medical records of patients who received PE therapy in the ICU between 1 January 2002 and 31 December 2011. Eligible patients were identified using a computerised search of the password protected Australasian Outcomes Research Tool for Intensive Care (AORTIC software V 9.2.3, Metafacts PTY LTD, Sydney, Australia) database, using the key term ‘plasma exchange’.5 No exclusions were applied. Therefore our key aims were to review and critique our use of PE for: the incidence, clinical indications, treatments prescribed and administered, any procedural or patient complications, and adherence to current best practice recommendations. Data was collected from the identified patient records using a purpose designed case report form. Patient demographic data sourced included: age, gender, admission diagnosis, acute physiology and chronic health evaluation (APACHE) III score, length of ICU and hospital stay. The procedural data collected for each patient included: indication for implementation, treatment duration, type and amount of replacement fluids, incidence of clotting, and any procedural or patient complications. Outcome data for survival and discharge location was also determined. Documents reviewed for data collection in this audit included: daily progress notes and discharge summary, ICU observation charts, drug and therapy orders, ICU medical round notes, and intravenous therapy order forms. One researcher collected and de-identified all data and referred to a senior researcher when clarification was required to manage any difficulties interpreting the clinical documentation.
Fig. 1. Number of patients receiving PE 2002–2011.
in the annual use of PE over the 10 years, as represented in Fig. 1. Demographic data for these patients is presented in Table 1. The median age of patients was 59.5 (48–70) years, of which there were 18 females. Median length of ICU admission was 9.5 (3–17) days. The median APACHE III score for patients in the audit was 62.5 (55–84), which is consistent with critical illness managed in a tertiary ICU.6 PE was indicated for multiple different diseases, with TTP associated illness being the most common (11 patients). The frequency of all presentations is further illustrated in Fig. 2. Plasma exchange procedure During this 10 year period, 135 PE procedures were completed. The median number of treatments per patient per ICU admission was four (2–5). The timeframe for treatment duration varied, however the most common was 6 h (62 treatments), followed by a 4 h duration used in 21 treatments. Some of the treatment durations were unable to be found in patient medical records due to data not being recorded. Of the 135 PE treatments analysed in this audit, 103 (76%) where prescribed at a 3 L exchange volume (range 1–5 L). In addition, this audit found the most commonly used replacement fluid was fresh frozen plasma (FFP) in 40 treatments. This may be in association with the high incidence of TTP, which was managed with fresh frozen plasma as the predominant replacement fluid. The next most common treatment regimen, used in 26 treatments, was 50% fresh frozen plasma and 50% human albumin 4%. Other common regimens included mixtures of 66.6% FFP and 33.3% human albumin 4% in 19 treatments, and mixtures of 33.3% FFP and 66.6% human albumin 4% in 18 treatments. Overall,
Data analysis Statistical analysis was performed using SAS version 9.2 (SAS Institute Inc, Cary, NC). Category variables would be expressed as frequency or number and percentage (%), and continuous variables that are normally distributed using mean ± standard deviation (±SD). When data was not normally distributed, median with 25th and 75th interquartile range (IQR) was used. Results The audit identified 30 patients who received PE in the ICU over the 10 year period. Total ICU admissions for this period were 19,728 resulting in a 0.15% incidence for the use of PE. There was no trend
Fig. 2. Indications for PE: illness & frequency.
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Table 1 Demographic data for the 30 patients where PE was prescribed. Reason for ICU admission
Gender M/F
Age
APACHE III
Medical Emergency Team (MET) call – ongoing seizures Post liver transplant Hypercapnic respiratory failure – requiring intubation MET call/CODE BLUE – respiratory distress – requiring intubation Guillain-Barré Syndrome (GBS) – requiring respiratory support Thrombotic Thrombocytopenic Pupura (TTP) – requiring plasma exchange Respiratory failure MET call – exacerbation of Myasthenia Gravis (MG) MET call – respiratory distress Hypoxia Transfer from another hospital – septic shock TTP – requiring plasma exchange MET call–hypoxia Transfer from another hospital – respiratory failure – history of MG Possible TTP Post liver transplant Altered conscious state MET call – status epilepticus – requiring intubation ICU review – increased malena, decreased haemoglobin despite transfusions Status epilepticus Transfer from another hospital – severe anaemia – for plasma exchange Pancreatitis Relapsed TTP – for plasma exchange MET call – respiratory failure TTP Post coronary artery bypass grafts ×5 Post liver and kidney transplant Post mitral valve replacement redo Fulminant liver failure Erythropoetic protporphyria–pre liver transplant
F F F M F M F F F M M M F F F F F F M F M M M M F M F F M F
66 42 78 54 71 57 77 60 64 68 44 43 79 68 45 62 75 59 64 23 49 48 47 70 51 75 54 71 59 22
61 52 52 59 60 132 63 50 61 68 123 41 97 84 39 57 88 62 73 55 71 98 38 93 37 86 61 72 66 65
Number (/) or median value and (25–75th) IQR
12/18
59.5 (48–70)
a combination of different replacement fluids was the preferred prescription regimen as identified in 91 (67%) PE treatments. This may be attributed to prescribing doctors aiming to imitate normal plasma constituents as much as possible in the replacement fluid. The remaining exchanges were prescribed with a single replacement fluid; FFP in 40 regimens, and human albumin 4% in the remaining four. Technical aspects of PE treatment This audit showed that more than one plasma membrane was required to complete some treatments. This was a result of blood clot formation in the extracorporeal circuit. For the 135 ordered PE treatments, 156 PE membranes were used to complete the prescribed therapy. Early cessation of PE therapy due to coagulation in the extracorporeal circuit occurred 21 times (15.5%) which resulted in a new circuit being primed to complete the PE therapy. Vascular access was also a complication that disrupted the PE procedure. In some instances the access catheter required replacement before PE therapy could be recommenced, resulting in treatment delay. The use of anticoagulation therapy during PE treatments was poorly documented. Therefore, if no documentation was found it was assumed that no anticoagulation was administered. Of the 156 PE treatments, 52 records showed that heparin was given for 10 different patients receiving PE therapy. Another two patients were receiving Dextran 40 (an antithrombotic) at the time of PE. Furthermore, of the 21 membranes that clotted there were six incidences where the patient was already receiving heparin. Discussion We report data from an audit of PE use in our ICU over 10 years. There were 11 different indications in the identified 30 patients
62.5 (55–84)
Length of stay ICU
Hospital
10 2 9 15 44 6 17 4 4 10 19 2 7 11 4 2 10 3 2 25 9 20 3 23 1 17 10 17 13 2
43 24 102 62 152 44 44 73 22 33 76 32 45 22 12 26 18 37 27 74 10 24 6 27 15 17 86 29 33 10
9.5 (3–17)
30.5 (22–45)
for the use of PE, with TTP being the indication in 37%. Only one other similar report was identified in the literature, also in a single centre over 10 years, reflecting a much higher use of PE with 330 patients and 1188 PE treatments. A key finding of this retrospective clinical study was the use of PE to manage sepsis; 46% of patients.7 A severity of illness score was not provided, however an overall mortality rate of 54.1% was reported.7 In our study, the median APACHE III score was 62.5 indicating a medium level of illness severity.8 Of the 30 patients six died in ICU; a 20% ICU mortality rate.
Thrombotic Thrombocytopenic Purpura Thrombotic Thrombocytopenic Purpura (TTP) was the most common indication for PE therapy. Eleven patients were suspected to have TTP. Five patients received FFP as sole the replacement fluid, which is in concurrence with the current best practice ASFA guidelines.4 The remaining six patients received a combination of FFP and human albumin 4%. The most common treatment time was 6 h. There is no recommended duration of treatment identified in the literature. Patients with TTP in this audit received a 3–4 L volume exchange which is approximately one plasma volume, depending on the patient’s weight which is in accordance with current recommendations.1,4,9,10 The results of this audit show that the recommended volume of PE was administered however, the type of fluid used for each treatment was not always consistent with current best practice recommendations.4,9,11 This audit was not focused to identify improvements in the patient’s symptoms following PE therapy. However, eight of the patients admitted for the management of TTP were discharged from hospital. The remaining three patients did not survive their ICU admission.
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Peripheral neurological disorders
ABO incompatible organ transplantation
This audit identified five patients with peripheral neurological disorders. Three patients required PE for the treatment of Myasthenia Gravis (MG), and two for the management of Guillain-Barré Syndrome (GBS). Both patients with GBS were treated with two cycles of PE therapy, each cycle consisted of consecutive daily PE treatments over either four or five days. All of the 18 PE treatments involved a 3 L exchange using a mixture of FFP and human albumin 4%, which was administered over a 3–6 h period. This identifies that some treatments did not follow current best practice recommendations which suggest the implementation of 5–6 s daily PE treatments with human albumin 4% as the sole replacement fluid.4,12,13 The three patients that required PE for the management of MG were administered 3 L or 5 L exchanges with a mixture of FFP and human albumin 4% or human albumin 4% alone over a 6–14 h period. PE was administered daily with FFP frequently used as a portion of the replacement fluid. Current best practice guidelines recommend the use of daily or second daily PE therapy with human albumin 4% as the sole replacement fluid for management of patients with MG.4,14–17 This identifies a difference between clinical practice and the literature reviewed which may need to be taken into consideration for future patients. Compliance to current ASFA recommendations could be improved with the implementation of an updated plasma exchange protocol in our ICU.
Four patients were identified by this audit to have received PE post organ transplantation and one patient pre organ transplantation. The two patients that received PE post organ transplantation required only one treatment, the exchanges were either FFP and human albumin 4% or FFP alone. Both of these patients received a 3 L PE regimen over 6 h. The other two patients that received PE post organ transplantation required four or five PE treatments which exchanged 1–4 L of plasma with either FFP alone or FFP and human albumin 4% over a 1–6 h timeframe. The patient that received PE pre organ transplantation was administered one treatment to remove 3 L of plasma, replaced with human albumin 4% over a 4 h period. The current best practice recommendations suggest PE regimens with albumin 4% as the sole replacement fluid unless severe coagulopathy is present.4,22,23 Of these five patients that received PE related to organ transplantation, four patients were discharged home and one was transferred to another hospital.
Renal disorders The category of renal disorders incorporates multiple different illnesses including; Waldenström’s Macroglobulinemia (WM), Anti-Neutrophil Cyroplasmic Antibody (ANCA), and antiglomerular basement membrane disease (anti-GBM). One patient was admitted to the ICU with suspected WM. This patient received three 4 L PE treatments which were replaced with varying combinations of human albumin 4%, FFP and plasmalyte over a 6 h timeframe. The current guidelines for the management of WM recommend human albumin 4% as the primary replacement fluid.4,18 Therefore the PE regimen was not in accordance with current best practice guidelines for patients with WM.4,18,19 This patient died in the ICU, however other aspects of the patient’s condition were not the focus of this audit such that PE should not be considered an ineffective treatment option for patients with WM. Two patients in this audit presented to the ICU with ANCA and received daily PE for five and seven days. Both these patients were prescribed a regimen of 3 L FFP or a mixture of FFP and human albumin 4% over a 3–6 h period. The ASFA recommend the use of albumin 4% in patients with ANCA, therefore this aspect of the treatment regimen was not in accordance with the current best practice ASFA guidelines.4 In addition, three patients required PE therapy for the treatment of anti-GBM disease. One patient was administered PE that failed to complete due to clotting in the extracorporeal circuit and was not recommenced. This patient also died in the ICU indicating that there may have been other clinical factors affecting their outcome. The other two patients with anit-GBM disease received daily PE treatments for 4 or 16 days. The regimen implemented for these two patients utilised a 3 L exchange that was replaced with a mixture of FFP and human albumin 4% over 6 h. The administered exchange volume and frequency for these two patients was in accordance with current best practice recommendations, however the recommended replacement fluid is albumin 4% which was not the sole replacement fluid administered for these two patients.4,20,21 One of these patients was discharged home and the other discharged to a rehabilitation facility.
Summary of discussion This 10 year retrospective audit has provided insight into the use of PE therapy in our ICU. Inconsistency in the prescription of PE therapy between patients and within a single patient implies that current best practice recommendations were not the influencing factor for prescribing PE. This indicates that either uncertainty and or past clinician experience may be the underlying reason for the choice of the PE regimen rather than reference to current best practice guidelines. The majority of patients reviewed in this study were discharged home or to a rehabilitation facility. Large cohort studies comparing different techniques for PE are difficult to implement in a single centre due to the rarity of the illnesses requiring PE therapy. Therefore, future studies would benefit from being multicentre to enable greater patient numbers, which would allow for a more robust study powered to test a comparative study hypothesis with conclusions for best practice accordingly. Following our audit and review of the literature, we recommend 1. Implement a simple, succinct prescribing document. Table 2 provides suitable information for prescribing and implementing PE in the ICU with evidence cited accordingly. This will assist doctors and nurses to ensure the regimen is correctly prescribed, implemented and well recorded in patient medical records. 2. Ensure the PE current best practice guidelines4 and hospital protocol are in an accessible location for all staff (paper or electronic). 3. Provide areas for documentation of anticoagulation and any adverse events during PE in ICU charts or electronic notes. 4. Higher doses of anticoagulation may reduce clotting during PE. This will reduce costs and nursing time where two membranes and circuits are needed to complete one treatment. Heparin or any drug used will be cleared at a higher rate with both watersoluble and protein bound losses occurring during PE. 5. Avoid delays on commencing PE in critically ill patients. PE appears to be a safe and well tolerated treatment in the ICU. Limitations This audit was limited by the small number of patients identified, and the retrospective nature of the study. All treatments were critiqued against current best practice recommendations which may have influenced our findings. Documentation of the PE regimen was not easily found and was often split over multiple different hospital medical records and charts in the ICU. Complications reported were not pre defined and this may have influenced our
Please cite this article in press as: Paton E, Baldwin IC. Plasma exchange in the intensive care unit: A 10 year retrospective audit. Aust Crit Care (2013), http://dx.doi.org/10.1016/j.aucc.2013.10.001
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Table 2 Information for prescribing and implementing PE in the ICU. Disease or illness
Substance for removal
Thrombotic Thrombocytopenic Purpura (TTP)
Antibodies that inhibit ADAMTS13
Guillain-Barré Syndrome (GBS)
Antibodies
Myasthenia Gravis (MG) NB 2nd line or treatment in a crisis
Acetylcholine receptor (AChR) antibodies
Waldenström’s Macroglobulinemia (WM)
Immunoglobulin (IgM)
Anti-glomerular basement membrane (anti-GBM) disease Overdose or poisoning
Anti-GBM antibodies
Protein bound toxins
ABO incompatible (ABOi) transplant
Anti-A and/or Anti-B antibodies
Rationale
Suggested regimen
A deficiency of ADAMTS13 enzyme is a result of auto-antibodies24,25 Prompt commencement is most effective4,12 PE is fast acting (days) with a short duration of action (weeks).16 Most beneficial in a myasthenic crisis or as a bridging tool16 Increased IgM creates hyperviscosity.18 A single PV exchange will reduce circulating IgM by 50–60%1 PE therapy removes anti-GBM antibodies therefore reversing the effect of the disease21 PE therapy removes highly protein bound toxins, but limited by unique characteristics of toxins4 PE therapy can reverse the clinical and pathologic manifestations of rejection4,23
Fluid
Amounta
Frequency
FFP4,9,11
4–6 L 1–1.5 PV4,9,10
Daily or twice daily4,9,10
Albumin1,4,12
4–6 L 1–1.5 PV4,13 4–6 L 1–1.5 PV4,15–17
2nd daily4
Albumin1,4,18
4–6 L 1–1.5 PV1,4,18
Daily4
Albumin4,11,21
4–6 L 1–1.5 PV4
Daily4,11,21
Albumin4
4–8 L 1–2 PV4
Daily4
Albumin22,23
4–6 L 1–1.5 PV4,22,23
2nd daily pre transplant22,23 daily or 2nd daily post transplant4
Albumin4,14
2nd daily15–17
PV, plasma volumes; FFP, fresh frozen plasma (containing ADAMTS13 enzymes); CNS, central nervous system. a Volumes are given based on an 80 kg person (one plasma volume = 50 ml/kg).
findings for this study aim. To allow for adequate data to be collected, assumptions were made from the partial documentation on the multiple documents within the patients’ medical files to establish specific parts of the implemented PE regimen.
Conflicts of interest None to declare. Authors’ contributions
Strengths This audit for the use of PE in our ICU has not been previously done. This audit gives insight into our ICU with PE therapy over a 10 year period where data and adherence to clinical recommendations in the literature is lacking. We provide clinical recommendations to improve the use of PE in our ICU and others. This may also contribute to improvement in patient outcomes if PE therapy is implemented in accordance with these recommendations. Conclusion Plasma exchange is an infrequent procedure in the ICU. TTP was the most common clinical indication for PE. Coagulation in the extracorporeal circuit resulting in broken treatment procedures is a clinical challenge in providing PE, however our audit suggests it is a safe treatment for critically ill patients when required. This audit also supports the rationale for early commencement of treatment before test results have confirmed the nature of the illness, as the risks associated with PE therapy appear to be less than those associated with the potential delay in treatment in many patients. As prescribing recommendations were not always followed, the implementation of a succinct documentation and prescription protocol for PE would ensure that current best practice recommendations are easily accessible and may improve outcomes for PE in the ICU. Ethical approval This study was approved as an audit activity by the Austin Health Office for Research. The HREC approval number is H2012/04795.
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