Therapeutic plasma exchange for the management of hypertriglyceridemia-induced acute pancreatitis
Do Thanh Hoa1, Nguyen Gia Binh2, Le Thi Viet Hoa3, Nguyen Hai Ghi1, Le Xuan Duong1
1 Emergency Department, 108 Military Central Hospital, Hanoi, Vietnam
2 Intensive Care Unit, Bach Mai Hospital, Hanoi, Vietnam
3 Intensive Care Unit, Tam Anh Hospital, Hanoi, Vietnam
Date of Submission 02-Jun-2021
Date of Acceptance 30-Jan-2022
Date of Web Publication 17-Aug-2022
BACKGROUND: Hypertriglyceridemia (HTG) is the third-most important cause of acute pancreatitis (AP) and its early diagnosis is essential to prevent AP-associated morbidity and mortality. Therapeutic plasma exchange (TPE) is a promising treatment option for improving patient outcomes and prognosis in HTG-induced AP (HTG-AP).
OBJECTIVE: This study assessed the severity of disease in patients with HTG-AP and evaluated the therapeutic effects, safety, and procedural challenges of TPE in its management.
METHODS: Patients with HTG-AP, diagnosed according to the Atlanta classification, and exhibiting serum triglyceride (TG) concentrations ≥11.3 mmol/L were included in the study. Consenting patients received TPE using the PRISMAFLEX® system (TPE group), and the remaining were treated in accordance with the guidelines of Vietnam's Ministry of Health, 2015 (non-TPE group). The duration of hospital or intensive care unit (ICU) stay in patients and mortality rates were compared between the TPE and non-TPE groups. The reduction in serum TG levels was also evaluated in the TPE group.
RESULTS: This prospective study included 165 patients with HTG-AP (n = 83, TPE group; n = 82, non-TPE group). The mean age of the patients was 41.0 ± 9.3 years. The duration of hospital and ICU stay was significantly lower in the TPE group compared to that of the non-TPE group (P < 0.05). A significant reduction in TG levels over baseline was noted in patients who received TPE (77%; P < 0.05), which was observed after the first TPE session (70.81%; P < 0.05).
CONCLUSION: TPE using the PRISMAFLEX® system is safe and well-tolerated in patients with HTG-AP and is associated with minimal technical constraints.
Keywords: Acute pancreatitis, hospitalization, hypertriglyceridemia, therapeutic plasma exchange, triglycerides
Hoa DT, Binh NG, Hoa LT, Ghi NH, Duong LX. Therapeutic plasma exchange for the management of hypertriglyceridemia-induced acute pancreatitis. Asian J Transfus Sci [Epub ahead of print] [cited 2023 Feb 2]. Available from: https://www.ajts.org/preprintarticle.asp?id=353988
Hypertriglyceridemia (HTG) is the third-most common cause of acute pancreatitis (AP) after alcohol consumption and gallstone disease, and accounts for up to 1%–10% of all AP cases. The risk of developing AP increases with higher triglyceride (TG) levels – 5% risk of AP at 1000 mg/dL (11.3 mmol/L) of TG and 10%–20% risk of AP at TG levels >2000 mg/dL (22.6 mmol/L).[1] Studies have indicated a 4% increase in the incidence of AP with every 100 mg/dL (1.13 mmol/L) increase in TG concentrations.[2] A meta-analysis, performed to investigate the association between TG levels and prognosis of AP, concluded that high serum TG levels were related to a worse prognosis of AP. Patients with HTG -induced AP (HTG-AP) exhibited a statistically significant risk for renal failure, systemic inflammatory response syndrome, and respiratory failure and shock, compared with patients having AP due to other causes (non-HTG–AP). Mortality associated with HTG-AP was also significantly higher (P < 0.01) compared with that associated with non-HTG-AP.[3]
The pathophysiological mechanism of HTG-AP has been postulated in two theories. In one of the proposed theories, high levels of circulating TG could result in higher concentrations of free fatty acids (FFAs), which in turn overwhelm the binding capacity of albumin. The FFAs self-aggregate into micellar structures, thereby promoting acinar cell and pancreatic capillary injury, and causing ischemia and acidosis. These processes trigger acute pancreatic inflammation. Alternatively, elevated TG levels result in an increased circulation of chylomicrons, which may increase plasma viscosity. Hyperviscosity, followed by ischemia, capillary clogging, and acidosis, may also play a decisive role in triggering HTG-AP.[4]
Therefore, early identification and treatment are crucial for controlling further complications of HTG-AP. The standard treatment approaches in the management of HTG-AP often involve fluid resuscitation; restrictions in oral intake; offering organ support; coupled with symptomatic management and pharmacologic therapies such as fibrates, statins, nicotinic acid derivatives, omega-3 fatty acids, and insulin. In addition, lifestyle modifications and dietary interventions are also recommended.[5],[6] Oral lipid-lowering therapy is generally considered in patients who are tolerant and ready for oral intake. Fibrates are recommended as the first-line therapy.[5] Plasmapheresis is used to reduce the levels of circulating chylomicrons.[7]
Therapeutic plasma exchange (TPE) is increasingly being considered as a relevant and practical option for several medical conditions related to neurology, hematology, and renal and metabolic diseases.[8] With the advantage of rapid lowering of TG levels within a short duration, TPE, if appropriately used, minimizes the chances of AP and prevents cardiovascular complications[9] Moreover, TPE can also improve the prognosis of AP by potentiating the elimination of inflammatory cytokines.[10] A recent review reported that TPE may be considered for patients with HTG-AP, based on their tolerance.[5]
There is a need for real-world studies on the use of TPE in the management of HTG-AP. We intended to bridge the existing knowledge gap by evaluating the clinical effectiveness of TPE in HTG-AP in real-world settings. We assessed the relationship between HTG levels and disease severity, in addition to the safety aspects of this procedure in patients.
This was a prospective, nonrandomized, open-label, single-center, comparative study. Patients diagnosed with HTG-AP at the Department of Intensive Care, Bach Mai Hospital, Vietnam, between December 2015 and May 2019, were included in this study. The study protocol was approved by the Medical Ethics Committee of Bach Mai Hospital, and informed consent was obtained from the patients. Patient selection was done based on the inclusion and exclusion criteria. The diagnosis of AP and classification of patients based on the severity of AP were carried out as per the revised Atlanta classification criteria.[11] Patients with typical abdominal pain, increased amylase and/or blood lipase (>3 times higher than normal values), or TG concentrations ≥1000 mg/dL (11.3 mmol/L) were included in the study. Other possible underlying causes of AP were excluded.
The study patients were not randomized and were assigned to each group based on their preference; patients provided informed consent to either receive TPE or regular therapy. Patients who received plasmapheresis via the PRISMAFLEX® system with the TPE 2000 set comprised the TPE group, whereas the non-TPE group, which served as the control, received standard care as per the guidelines of Vietnam's Ministry of Health, 2015 [Figure 1]. Patients were assigned to each group until there were an equal number of participants in both groups. Based on the severity of the disease, patients were further subcategorized into mild AP (MAP), moderately severe AP (MSAP), or severe AP (SAP) groups.
Figure 1: Guidelines of Vietnam's Ministry of Health, 2015. NSAIDs = Nonsteroidal anti-inflammatory drugs, PPI = Proton-pump inhibitors, VTC = Ventricular tachycardia
Plasmapheresis/therapeutic plasma exchange
The most convenient femoral vein was accessed to deliver plasmapheresis using the PRISMAFLEX® system with a TPE 2000 set under sterile conditions. During TPE with the PRISMAFLEX® system, negative pressure was created by the effluent pump to pull plasma across the TPE 2000 plasma filter membrane from the blood compartment and deliver the plasma into the effluent bag. At the same time, a prescribed replacement solution of 0.9% sodium chloride solution with 5000 UI/1000 mL heparin phase was infused into the patients' blood postfilter via the replacement pump. The volume of plasma replacement was 40 mL/kg/hour for patients with a normal hematocrit. For patients with a lower-than-normal hematocrit, the plasma volume was larger because it was not reduced. Plasma or replacement fluid was kept warm at 37°C. The removal of plasma was at a rate of 20 mL/min.
Following catheterization, plasmapheresis was initiated in patients in the TPE group using a PRISMAFLEX® (Baxter) system with TPE 2000 filters. Plasmapheresis was administered at the earliest time point from disease detection (<24–48 h) and was continued until TG levels dropped to <500 mg/dL (5.65 mmol/dL).[12] Based on the reduction in TG levels and patient outcomes, additional TPE sessions were conducted until the desired TG levels were achieved.
The efficacy of TPE in improving outcomes in patients with HTG-AP, in addition to its safety aspects, was assessed in this study.
Efficacy assessments
A comparative assessment of sequential organ failure assessment (SOFA) and Ranson score over time of hospitalization was performed in both groups. The scores were used for severity stratification and prognostic prediction of patients with AP at an early phase. The duration of hospitalization, length of stay in the intensive care unit (ICU), and in-hospital mortality rates were compared between the groups. In the TPE group, change in serum TG levels was assessed before and after the first, second, and third TPE sessions and on the 28th day postdischarge. Cholesterol levels were assessed from day 1 of hospitalization until discharge.
The incidence of TPE-related immunogenic and allergic complications, if any, such as electrolyte disorders (raised or reduced sodium and blood potassium levels), infections, irregular adjacent catheter bleeding, gastrointestinal bleeding, systemic hemorrhage, or other complications, was recorded.
Procedural assessments
Technical constraints, if any, impeding the smooth delivery of TPE, such as coagulation of filters, membrane ruptures, occlusions in the catheter, catheter fractures, and stamping of catheters, were recorded, monitored, and assessed.
Sample size estimations were performed to include 69 patients in each group. Considering estimations on the number of patients who could withdraw or drop out, an additional 10 patients were included in each group.
Analysis was performed using Statistical Package for Social Sciences, version 22.0 (SPSS Inc., Chicago, IL, USA). Data were expressed as a percentage, mean ± standard deviation (SD), and median. A Chi-squared test was performed to compare qualitative data; descriptive statistics are shown in %. Statistical significance was considered at P < 0.05.
A total of 182 patients were screened, of which 10 patients were excluded and 7 dropped out. A total of 165 patients diagnosed with HTG-AP and exhibiting elevated TG levels (≥1000 mg/dL/11.3 mmol/L) were included in this study. Of these, 83 patients received TPE with the PRISMAFLEX® system, whereas the remaining 82 patients were treated according to the guidelines presented in [Figure 1].
The baseline characteristics of patients in this study are listed in [Table 1]. The mean age of the patients was similar in TPE (40.2 ± 9.0 years) and non-TPE groups (41.9 ± 9.5 years). Approximately 36.1% and 51.2% of the patients in the TPE and non-TPE groups, respectively, had a history of alcoholism. Hyperlipidemia was reported in 44.6% and 54.9% of patients in the TPE and non-TPE groups, respectively.
Table 1: Patient demographics and clinical characteristics in the therapeutic plasma exchange and nontherapeutic plasma exchange groups
Overall, a higher proportion of patients had MAP (40%), whereas the remaining patients had either MSAP (35.2%) or SAP (24.8%). For the representation of results, the SAP and MSAP groups were considered collectively as moderate and severe AP in this study.
The estimated SOFA scores revealed a positive correlation (correlation coefficient r = 0.35, P < 0.05) between TG levels and disease severity in HTG-AP.
Comparative assessment of days of hospitalization, intensive care unit stay, and mortality rate in therapeutic plasma exchange versus nontherapeutic plasma exchange groups
The average duration of hospitalization and length of stay in the ICU were significantly lower (P < 0.05) in patients who underwent TPE than those in the non-TPE group, as shown in [Table 2]. The mean (±SD) duration for hospitalization in TPE and non-TPE groups was 7.5 ± 5.33 and 10.1 ± 6.31 days, respectively. Within the subgroups, a significant difference in the duration of hospitalization was recorded in patients with MSAP (P < 0.05). Although the average length of ICU stay and hospitalization were lower in patients with MAP in the TPE group, the difference was not statistically significant compared with the non-TPE group. Mortality was recorded in three patients in the non-TPE group, whereas no mortality was observed in the TPE group.
Table 2: Comparison of duration of hospitalization stay and intensive care unit stay between therapeutic plasma exchange and nontherapeutic plasma exchange groups
SOFA and Ranson scores were similar in both groups at baseline (at the time of hospitalization). However, on day 2, the SOFA score was significantly lower in the TPE group compared with that in the non-TPE group (P < 0.05) [Figure 2]. There was no significant difference in the Ranson score between the groups throughout hospitalization.
Figure 2: Comparison of sequential organ failure assessment scores in TPE versus non-TPE groups. TPE = Therapeutic plasma exchange, SOFA = Sequential organ failure assessment
Comparative evaluation of serum triglyceride levels before and after therapeutic plasma exchange
Serum TG levels recorded before and after TPE are presented in [Table 3]. There was a significant reduction (70.81%; P < 0.05) in TG levels after the first TPE session. The mean TG levels reduced significantly from 31.87 ± 27.93 mmol/L (before TPE) to 9.30 ± 5.07 mmol/L after the first TPE session (P < 0.05). Only 8 out of 83 patients who received TPE required a second session, whereas only 1 patient required an additional third session [Table 3]. The reduction in TG levels was significant across the TPE sessions (P < 0.05). The reduction in TG levels was greater in the MASP subgroup as compared with patients with MAP (69.9% and 66.5%, respectively).
Table 3: Mean serum triglyceride levels across therapeutic plasma exchange sessions
TG levels were recorded and re-examined 28 days after hospital discharge in 120 patients. The mean TG level in the TPE group (5.12 ± 2.24) was significantly lower than that of the non-TPE group (7.21 ± 3.11, P < 0.05). The mean serum TG and cholesterol levels assessed in the TPE group during hospital stay were significantly different between the MASP and MAP subgroups only on day 1 of hospitalization. On the subsequent days until discharge, the difference in values between the subgroups was nonsignificant [Table 4].
Table 4: Mean change in serum triglyceride and cholesterol levels across severity of acute pancreatitis in the therapeutic plasma exchange group
TG levels decreased from ~ 35 mmol/L and 21 mmol/L at day 0 to 3.20 mmol/L and 5.33 mmol/L before hospital discharge in the TPE and non-TPE groups, respectively [Figure 3].
Figure 3: Changes in TG levels during hospitalization in TPE and non-TPE groups. TG = Triglyceride, TPE = Therapeutic plasma exchange
There were no significant differences in the mean serum TG and cholesterol levels in the non-TPE group during hospital stay between the MASP and MAP subgroups [Table 5].
Table 5: Mean change in serum triglycerides and cholesterol levels across severity of acute pancreatitis in the nontherapeutic plasma exchange group
Approximately 19% of the patients started receiving TPE within 6 h after hospital admission. Within <24 h after getting admitted, approximately 42% of the patients received TPE [Figure 4].
Figure 4: Percentage of patients receiving TPE after hospital admission. TPE = Therapeutic plasma exchange
In addition, the time of initiation of TPE also impacted the change in TG levels. Early initiation of TPE, i.e., within 24 h of detection of HTG-AP, resulted in a faster TG reduction, as compared to initiation of TPE at a later period (after >24 h of detection).
Safety outcome of therapeutic plasma exchange administration in patients with hypertriglyceridemia-acute pancreatitis
A total of 93 cumulative TPE sessions were administered, with each patient receiving a minimum of one TPE session (n = 83). Only eight patients required two sessions, whereas only one patient received three sessions to achieve the desired serum TG levels (<500 mg/dL/5.65 mmol/dL).
Anaphylaxis degree I reaction was noticed in 11 instances out of the overall 93 TPE sessions administered (11.8%). These were recorded as systemic and local allergy presentations in the patients. The patients were managed well with appropriate medications (dimedrol, methylprednisolone) and stabilized. The most common electrolyte disorders encountered are shown in [Table 6].
Table 6: Summary of technical errors associated with the therapeutic plasma exchange system and complications associated with electrolyte disorders (safety-evaluable patients)
Procedural outcomes
The most common complication noted while performing TPE was the coagulation of filters, which accounted for 19.4% of the complications, as shown in [Table 6]. A majority of patients (98.8%) received heparin to overcome coagulation issues.
Our study demonstrated the beneficial effects of administering TPE to patients with HTG-AP. A rapid reduction of serum TG levels was achieved after the first TPE session (70.81% reduction). Administration of TPE significantly reduced the burden of hospitalization, ICU stay, and TG levels in patients with HTG-AP (P < 0.05). While our study demonstrated that early initiation of TPE results in better outcomes and early diagnosis, timely treatment with appropriate modalities remains a challenge in the management of HTG-AP.
A positive correlation between elevated TG levels (r = 0.26, P < 0.01) and disease severity in HTG-AP has already been established.[5],[13] This has been confirmed in the present study as well. Hence, several studies have emphasized the importance of lowering TG levels in the management of HTG-AP and in the prevention of associated morbidity and mortality.[5] Patients with HTG-AP exhibited elevated TG levels and were associated with a higher incidence of complications (35%–69%), organ failure (20%–35%), prolonged hospitalization, and high mortality rates. TG levels >11.3 mmol/L are an identifiable risk factor for AP.[5]
Conventional treatment (fasting, lipid-lowering drugs, insulin, or fluid restoration) may gradually decrease TG levels within a period of days to weeks.[14] In contrast, plasmapheresis/TPE results in the rapid removal of excessive lipids from the serum in about 2 h.[15],[16] Sporadic reports on the use of plasmapheresis in hyperlipidemic pancreatitis are available. These studies have documented the beneficial effects of plasmapheresis in HTG-AP[5],[6] However, to date, no study has systematically compared the effects of TPE versus standard care in patients with HTG-AP. In the present study, we assessed the therapeutic effects, safety, and procedural challenges of TPE for the treatment of HTG-AP.
A total of 93 TPE sessions were performed in 83 patients in our study. This is in accordance with the study by Gubensek et al., in which 50 patients with hyperglycemic pancreatitis received 79 TPE sessions in total. In this study, each patient received 1–5 TPE sessions.[17]
The extent of TG and cholesterol reduction was greater in our study as compared to that reported in Yeh et al.,[14] despite the small size of the cohort. The serum TG levels rapidly reached the desirable state after TPE. The reduction in TG and cholesterol levels was faster in the TPE group than that in the non-TPE group. There was a rapid reduction in TG levels within the first 24–48 h of TPE; this may be due to the compensation of fluid loss due to increased TG levels. In the present study, a replacement solution containing heparin was administered to the patients. Heparin infusions have been reported to stimulate lipoprotein lipase activity and decrease serum TG levels in AP.[18]
We also observed that early TPE treatment (<24 h postdetection) resulted in a rapid decrease in elevated TG levels as compared to that observed in late treatment (>24 h after detection). These findings highlight the importance of initiating TPE early in the management of HTG-AP, thereby reducing associated complications, mortality rate, days of hospitalization, and ICU stay. The TPE group exhibited a faster TG reduction rate than the non-TPE group because, at the time of admission, the TPE group had a higher TG level and a shorter hospital stay than the non-TPE group. Our study also demonstrated that the desired TG reduction could be achieved in a majority of patients with just one TPE session.
In our study, no mortality was reported in the TPE group; whereas three mortalities were reported in the non-TPE group. From our results, we propose that initiating TPE at the earliest, <24–48 h from the time of detection of AP, might be a critical factor in the management of HTG-AP, particularly in patients with MSAP.
The likely risks of allergic reactions and transfusion-related infections have remained a major setback in TPE.[11] Similarly, in our study, anaphylaxis was encountered in a few patients. However, these were of mild etiology and were adequately resolved.
We also examined procedural constraints commonly reported with TPE. In the 93 TPE sessions that were conducted, we found that the PRISMAFLEX® (Baxter) system with TPE 2000 filters was safe and effective for use in the treatment of HTG-AP. The PRISMAFLEX® system with TPE 2000 filters can remove target proteins of molecular weight between 1 and 3 million Da. TGs, cholesterol, and chylomicrons are well within this range for filtration using TPE.[16],[19]
We present real-world evidence on the use of TPE in a small number of patients with HTG-AP in Vietnam. Our study was limited in terms of study design and population. The present study included only a single center and did not have sufficient statistical power for extrapolation of the results. In addition, approximately two-thirds of the population was male, and the mean age was approximately 42 years, indicating that the findings cannot be generalized across age or gender. The administration of TPE was purely based on patient consent and a randomization technique was not followed. Therefore, possibilities of selection or observational bias cannot be eliminated. In addition, assessment of pre- and post-TPE APACHE scores and the effects of TPE on morbidity need to be established through a controlled study design. The effects of TPE may be assessed in a larger population, compared to a group receiving standard therapy. These studies would aid in the routine use of TPE for patients with HTG-AP. Moreover, further studies are necessary to establish reliable guidelines to ensure its long-term efficiency.
In summary, early initiation of TPE is safe and effective in the management of HTG-AP. A rapid reduction in serum TG levels could be achieved even with one TPE session in the majority of HTG-AP patients with moderate-to-severe disease. Furthermore, systematic, experimental studies in larger cohorts across geographical regions, in addition to real-world evidence, are needed to incorporate TPE for routine use in HTG-AP patients.
We would like to thank BioQuest Solutions for the editorial assistance.
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Do Thanh Hoa,
N01 Tran Hung Dao, Hanoi
DOI: 10.4103/ajts.ajts_67_21
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
[PREVo]
- Hoa DT
- Binh NG
- Hoa LT
- Ghi NH
- Duong LX