Initiation time of double-filtration plasma apheresis affects the risk of persistent organ failure in hypertriglyceridaemia-induced acute pancreatitis: a retrospective study – Scientific Reports

This study was conducted to understand the relationship between the timing of DFPP initiation and the risk of POF in an HTG-AP cohort in China. To our knowledge, this is the first study to incorporate initiation time into a measure of DFPP treatment and to analyse its impact on outcomes in HTG-AP patients. The principal finding of this study was that early initiation of DFPP treatment was able to reduce the risk of POF in HTG-AP patients. We found an increasing trend for the prevalence of POF with delayed DFPP treatment in the tertiles of DTD time. A similar increasing trend for the incidence of POF was found in the male, BMI ≥ 28 kg/m², pre-TG > 56.5 mmol/L and non-DKA subgroups with increasing tertiles of DTD time. Those associations persisted after adjustment for relevant potential confounding factors. In addition, we used multivariable regression analyses and RCS regression analyses and revealed nonlinear relationships between DTD time and the risk of POF in HTG-AP patients. HTG-AP patients had a relatively low risk of POF when a session of DFPP treatment was completed less than 15 h after diagnosis; since then, the risk of POF has increased rapidly with increasing DTD time.

It has been generally hypothesized that the therapeutic effect of DFPP treatment is based on the immediate physical extracorporeal elimination of TG-rich lipoproteins from plasma, subsequently reducing other pathophysiological processes of pancreatitis, such as inflammation, oxidative stress, and impaired rheology^4,5,12,13,14. Thus, the theoretical effect of DFPP was to instantly stop further organ damage and dysfunction in the setting of HTG-AP. Isabel and coworkers found a significant decrease in the APACHE II score after DFPP treatment in four patients with severe HTG-AP, which indicated a decrease in the severity of organ dysfunction²². Chang et al. performed nested case‒control studies for HTG-AP patients with or without DFPP. They concluded that DFPP could shorten hospitalization and reduce disease-related complications in HTG-AP patients with serum TG above 56.5 mmol/L (5000 mg/dL)²³. They also found that prophylactic DFPP reduced the incidence of recurrent HTG-AP, which had been reported in a previous study^23,24. They thought that the beneficial effect of DFPP therapy was not only due to the rapid reduction in serum triglycerides but also due to the removal of inflammatory lipoproteins (SAA1) and a decrease in oxidative stress²³. In this study, we showed a promising effect in reducing serum TG levels, which were decreased by 73.6% after a session of DFPP, in accordance with previous studies. We also found that early initiation of DFPP treatment could enable rapid TG reduction to below 5.65 mmol/L within 48 h as soon as possible, and earlier DFPP treatment was associated with lower SOFA_max and APACHE II scores at 48 h of admission and less hospital stay and charges. Importantly, after adjustment for potential confounders, the data from our study provided the first clinical evidence that early initiation of DFPP treatment could reduce the risk of POF.

However, the current evidence is too limited to identify the effect of DFPP on beneficial outcomes in HTG-AP patients. DFPP has never been recommended as the preferred treatment for HTG-AP by guidelines around the world because of inconsistent results in several clinical studies. Chen et al. compared two groups of patients before and after apheresis treatment in a large retrospective study and found no benefit on all-cause mortality and complications²⁸. They thought the reason was that the time of plasmapheresis might be the critical point. If patients with hyperlipidemic pancreatitis could receive plasma exchange as soon as possible, better result might be expected²⁸. If clinical therapy to remove TG from plasma is delayed, the damage from high levels of TG and its derived FFA persists, and a high risk of POF remains²⁹. In our study, all the HTG-AP patients with DFPP treatment achieved similar median TG levels and proportions of serum TG less than 5.65 mmol/L within 48 h of diagnosis, but patients with delayed DFPP treatment achieved a high incidence of POF. This means that delayed DFPP treatment loses its benefit of rapid TG clearance because persistent high levels of serum TG and FFA may have already damaged the pancreas and triggered systemic organ damage. The RCS curves showed that the optimal cut-off time for the preventive effect of DFPP treatment on POF was approximately 15 h after diagnosis. This time frame requires further investigation, but it suggests that the timing of DFPP initiation may be critical in reducing the risk of POF in HTG-AP patients.

The initial TG level should be taken into account when assessing the value of early initiation of DFPP in the treatment of HTG-AP. Lu et al. published a propensity score-matched retrospective comparison of HTG-AP patients treated with DFPP and without DFPP. They showed a 74.2% reduction in TG levels after a session of DFPP, similar to our study, but no beneficial effects on clinical outcomes between the groups²⁶. The reason for the negative conclusion was considered to be due to the difference in the initial TG levels³⁰. In Lu’s study, the mean TG levels in patients without DFPP treatment were reduced from 31.1 mmol/L (2755 mg/dL) on admission to 5.4 mmol/L (478 mg/dL) at 48 h, with no difference from those treated with DFPP. This meant that DFPP was not necessary because conservative management alone was able to reduce the TG levels sufficiently with such initial TG levels^26,30. In the subgroup of our study, we found that early DFPP treatment could reduce the risk of POF only in patients with pre-TG levels above 56.5 mmol/L (5000 mg/dL). This is because conservative management may become insufficient to reduce TG in a timely manner as initial TG levels become higher. In a study of conservative management in HTG-AP patients, the average TG level was reduced from 45.4 mmol/L on presentation to 13.3 mmol/L within 48 h, corresponding to a 48-h reduction of 69.8%, which was similar to a session of DFPP, but could still not keep the 48-h TG level away from the threshold for the risk of POF³¹. In this condition, it is reasonable to initiate early DFPP treatment for rapid TG lowering. It is necessary to focus on the initial TG level, which should be the indication for early initiation of DFPP in the treatment of HTG-AP.

In addition, the effect of early DFPP treatment on reducing the risk of POF may be influenced by the other initial conditions, which have been reported to be associated with the severity of AP. Males were found to have significantly worse clinical outcomes in AP³², and BMI ≥ 28 kg/m² might amplify the inflammatory response of pancreatic and peripancreatic tissue and increase the risk of organ failure^33,34. In our study, early DFPP treatment showed a significant trend to reduce the risk of POF in the male and obese subgroups but not in the female and nonobese subgroups. This suggests that early initiation of DFPP may be more meaningful for male patients or those with BMI ≥ 28 kg/m². Interestingly, it was reported that DM should aggravate the severity of AP^35,36, but in our study, the early completion of DFPP treatment was not significantly associated with a reduced risk of POF in the DKA subgroup with HTG-AP. As we used fluid infusion and insulin therapy to treat DKA in HTG-AP patients, which was also an effective TG-lowering treatment, the benefit of DFPP treatment might be attenuated. In conclusion, DFPP is one of the most important TG-lowering treatments in clinical practice. Early initiation of DFPP treatment is beneficial and preferred according to individual conditions such as pre-TG level, sex, BMI ≥ 28 kg/m² or other initial comorbidities.

However, our study also had several inherent limitations. First, we had no corresponding non-DFPP treatment group to provide direct comparison, so the study by default was restricted, and the results might be biased. Second, we chose the time from diagnosis to DFPP rather than the time from onset to DFPP because of the objectivity of the diagnosis time. The conclusion might be influenced by the bias of different individuals from onset to diagnosis time, although the role of this factor was attenuated by multivariate logistic regression. Third, our analyses of patients with HTGP were limited by relatively small sample sizes, which underpowered our ability to assess outcomes, especially the rare outcomes of in-hospital mortality and IPN. In addition, the patients enrolled in the study were from a large university-affiliated tertiary care hospital and could not represent the entire population of patients with HTG-AP; thus, the results cannot be generalized. Fourth, due to the retrospective nature of the study, it is subject to all the biases associated with retrospective studies. Therefore, the effect of DFPP on HTG-AP outcomes should be examined further in well-designed prospective studies or randomized clinical trials. Moreover, DFPP therapy was decided by the treating clinicians. Different DFPP treatment dosages were not discussed in this study, which needs further exploration.