Abstract
Background and aims: CPDF therapy is a blood purification therapy to support liver of critical patients with acute liver failure (ALF). There were no studies about the comparison of CPDF therapy and conventional therapy ,such as plasma exchange and hemodialysis. Therefore, we retrospectively compared CPDF therapy with conventional therapy in critical patients with ALF.
Hypothesis: We hypothesis that CPDF therapy would reduce mortality in patients with ALF compared with conventional therapy.
Methods: 30 patients with ALF underwent CPDF therapy (n =15) or conventional therapy (n =15) in the intensive care unit at Kanazawa University Hospital from November 2007 to November 2016. The baseline characteristics of the groups were similar. The CPDF therapy and conventional therapy were undergone for 3-5 days. Fresh frozen plasma (FFP) was infused at 120 mL/h in CPDF therapy and was infused at 1200 mL/h for 4 hours in conventional therapy. Primary outcomes were 14-day and 56-day survival rate after therapy. Secondary outcomes were liver function (ALT, bilirubin, INR and MELD scores) at days 0, 1, 3 and 5, and sequential organ failure assessment (SOFA) scores at days 0, and 7.
Results: 14-day and 56-day survival rate were significantly higher in CPDF therapy group than in conventional therapy group ([100% vs. 73.3%, P = 0.038], [73.3% vs. 33.3%, P = 0.019], respectively). CPDF therapy significantly improved ALT, bilirubin, INR and MELD score after treatment (P = 0.040, P = 0.033, P < 0.001, P = 0.044, respectively). However, no significant differences were noted in liver function and SOFA scores between two therapies.
Conclusion: CPDF therapy had advantages of 14-day and 56-day survival, easier preparation and lower dose of FFP compared with conventional therapy, and significantly improved liver function and severity after treatment. This study suggested that CPDF therapy may be a new alternative therapy to conventional therapy. (299 words)
Introduction
Acute liver failure (ALF) is the clinical manifestation of jaundice, ascites, hepatic encephalopathy, multi organ failure due to disorder of hepatic metabolic and immunological function. ALF is associated with high mortality and resource cost. (1)
Survival in ALF patients has improved over the last three decades but a high mortality remains(2, 3) . There is room for improvement to the treatment of patients with ALF. The initial approach to ALF management includes intensive care support and appropriate assessment for liver transplantation, such as King’s College Criteria, Clichy Criteria, and Japanese Criteria. Liver transplantation is the first line therapy in many countries for those patients with ALF who fulfill criteria as a poor prognosis. However, liver transplantation is not universally available and therefore there is necessary for alternative therapies to reinstate and reserve vital organ function and suppress the progression of MOF until spontaneous liver regeneration arises.
Alternative therapies include Artificial liver support systems (ALSS) and biloartificial liver support systems.
ALSS aim to remove of circulating toxic mediators which dissolved in water and bound to albumin. ALSS have been used to treat patients with ALF trying to bridge either to regeneration or to transplantation.
Currently, a variety of ALSS, including plasma exchange (PE), Hemodiafiltration (HDF), Plasma diafiltration (PDF), molecular adsorbent recirculating system (MARS), and some other methods, has been used to treat liver failure. Previous studies have demonstrated that the ALSS can significantly improve survival in acute liver failure. (4).
PDF therapy is a blood purification therapy that performs simple plasma exchange (PE) using a selective membrane plasma separator while the dialysate flows outside the hollow fibers. Previous study has shown that PDF therapy has advantages of medical economics and the removal of water-soluble and albumin-bound toxins, in the patients with ALF.
In order to reduce the influence on hemodynamics and maximize the effect, we developed continuous PDF (CPDF) therapy as a new concept in PDF therapy(5). Briefly, as an image, CPDF therapy was combined continuous slow PE therapy and CHDF therapy, and was performed using the same mechanism but different dialyzer and blood flow as CHDF therapy, and lower fresh frozen plasma (FFP) than PE therapy.
We previously reported that CPDF therapy significantly improved liver function and severity after treatment, and CPDF therapy is one of the most useful blood purification therapies in critical patients with ALF who combined multiple organ failure and unstable hemodynamics(5). Therefore, it is possible that CPDF therapy can be a new alternative therapy to conventional therapy. However, no study has been reported on the efficacy and outcome compared CPDF therapy with conventional therapy.
In this study, we hypothesized that CPDF therapy would reduce mortality in patients with ALF. We retrospectively compared CPDF therapy with conventional therapy in critical patients with ALF.
Materials and Methods
This study was conducted with the informed consent of the patients and families involved, and with the approval of the institutional ethical committee of the Kanazawa University Graduate School of Medicine. This study protocols conformed to the ethical guidelines in the 2013 Declaration of Helsinki.
Patients
Thirty patients (18 men and 12 women) with ALF were treated in the intensive care unit (ICU) at Kanazawa University Hospital from November 2007 to November 2016. No one have done liver transplant after treatment. The median age of the patients was 42 years (34-53 years). We divided the 30 severe ALF patients into two groups with the main therapy.
Acute liver failure was defined as the Japanese diagnostic criteria for ALF, which consists of plasma prothrombin time values of < 40% of the standardized value or prothrombin time international normalized ratios (INR) of > 1.5 caused by severe liver damage within 8 weeks of the onset of disease symptoms when prior liver function was estimated as normal.
CPDF therapy and conventional therapy were undergone for 3-5 days. Except for these therapies, prevention and treatment of clinical problems related to liver failure such as gastrointestinal bleeding, cerebral edema and infection was common to both groups. Circulatory access was established through a double lumen catheter via the patient’s jugular or femoral vein.
CPDF therapy
CPDF therapy was performed using an Evacure EC-2A plasma separator (Kuraray, Tokyo, Japan) at a blood flow rate of 80 mL/min. Filtered replacement fluid for dialysis (Sublood-BS; Fuso Pharmaceutical, Osaka, Japan) was infused at a dialysate flow rate of 400 mL/h and a replacement flow rate of 280 mL/h. FFP (Japanese Red Cross, Tokyo, Japan) was infused intravenously at 120 mL/h, and 50 mL of 25% albumin solution (Japan Blood Products Organization, Tokyo, Japan) was infused intravenously twice in 24h ,and nafamostat mesilate (Coahibitor; Ayphama, Tokyo, Japan) was used as an anticoagulant (Fig. 1).
Unless disabled, the CPDF column was replaced every 24–48 h. Patients were closely observed for signs and symptoms of side effects or complications during this treatment. We decided that the criteria for discontinuation of CPDF was a total bilirubin of < 5.0 mg/dL and INR < 1.2. TR-55X (Toray, Tokyo, Japan) was used for blood purification device.
Conventional therapy
Conventional therapy was defined as ALSS therapy such as plasma exchange (PE) therapy or hemodiafiltration (HDF) therapy.
PE therapy was used for abnormality of coagulation and immunologically-driven disorders, and HDF therapy was used for accumulation of toxic substances.
FFP was infused at 1200 mL/hr for 4 hours in PE therapy. Blood flow rates ranged from 150 to 180 mL/min in HDF therapy. If INR was less than 1.2 or the patient recovered from encephalopathy and disorientation disappeared, conventional therapy was discontinued.
Study endpoints
The primary endpoints were set to 14-day and 56-day survival rate after therapy as indicators of short and long term survival, respectively. The secondary endpoints were liver function measured by the model for end-stage liver disease (MELD) score, bilirubin, albumin, ammonia and INR at days 0, 1, 3 and 5, and sequential organ failure assessment (SOFA) scores at days 0, and 7. MELD score is predictive of survival and is used to prioritize patients with chronic liver disease for orthotopic liver transplantation (6) (7). MELD score is often used as one of more objective models for prioritizing patients based on liver disease severity. We used MELDNa score including serum sodium as a factor based on Organ Procurement and Transplantation Network Policy 9.1.
SOFA scores are used to predict outcomes of patients in ICU by assessing the severity of organ dysfunction based on six different scores, such as respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems (8) .
Statistical analysis
Data were expressed as mean ± standard deviation (SD). Chi square test and Student’s t-test were used to check the significance of the differences before and after treatment and between groups. Data were analyzed using SPSS 23.0 (SPSS Inc., Chicago, IL, USA). A Differences at p < 0.05 were deemed to be significant. Survival was estimated with the Kaplan-Meier method, and survival estimates were compared by using the log-rank test. Data were censored on November 23, 2016. Overall survival was calculated from the date of treatment to the date death from any cause.
Results
Patient Characteristics
CPDF therapy and conventional therapy were each 15 cases, respectively. The session time of CPDF therapy was significantly higher in CPDF therapy group than in conventional therapy group (P < 0.001), and the session time of conventional therapy was significantly higher in conventional therapy group (P < 0.001). There were no statistically significant differences in patient characteristics at baseline (demographic characteristics, etiology, neurologic status, disease severity, and liver and kidney function) between groups (Table 1).
Primary outcomes.
14-day survival rate was significantly higher in CPDF therapy group than in conventional therapy group (100% vs. 73.3%, respectively P = 0.038). And 56 days, the survival rate was also significantly higher in CPDF therapy group than in conventional therapy group (73.3% vs. 33.3%, respectively P = 0.019) (Figure 2).
Secondary outcomes.
No significant differences were noted in liver function including AST, ALT, albumin, INR, bilirubin and ammonia, liver severity for MELD score, and general severity for SOFA scores between two therapies after treatment (Figure 3). MELD score improved, bilirubin decreased, and INR decreased after two therapies. SOFA scores also decreased after two therapies except early death case. However, CPDF therapy significantly improved ALT from 485 to 93 (P = 0.040), total bilirubin from 19 to 7.4 (P = 0.033), INR from 1.98 to 1.33 (P < 0.001) and MELD score from 22.7 to 16.5 (P = 0.044) after treatment (Table 2). In addition, we could use these treatments without adverse events such as infection and unstable hemodynamics.
Discussion
Brief summary
In this study, we hypothesized that CPDF therapy would reduce mortality in patients with ALF. To support this hypothesis, CPDF therapy improved 14-day survival, 56-day survival, liver function and severity in critical ALF patients compared with conventional therapy without any adverse effects.
Comparison with previous studies
Previous studies have shown that CPDF therapy significantly improved liver function and severity including MELD score, total bilirubin and SOFA score after treatment, and ALSS can significantly improve survival in acute liver failure than SMT. This was the first study to compare CPDF therapy with conventional therapy and it was similar to the previous report in that CPDF therapy improved liver function and severity.
Possible explanations and implications
In this study, the primary endpoint was set to 14-day survival as an indicator of the period to liver transplantation and was set to 56-day survival as an index of liver regeneration.
Some reasons of survival improvement in CPDF therapy should be considered. First, CPDF therapy significantly improved liver function and severity after treatment. Liver function and liver severity have been reported to be associated with prognosis, consistent with this result. Second, although not significant, CPDF therapy group tended to have less viral diseases and lighter hepatic encephalopathy than conventional therapy group. Third, we did not consider subsequent therapy after initial treatment. Although there were reported that the prognosis of viral disease was good, differences in subsequent treatment based on etiology may have affected.
About CPDF therapy
Conventional PDF therapy is simple, less expensive, and with fewer adverse events than other treatments. As a result, this therapy has been demonstrated to be one of the most useful blood purification therapies for ALF patients(9, 10). However, conventional PDF therapy used intermittently throughout an 8-hr day is difficult to maintain the hemodynamic stability of severe ALF patients.
We have dealt with critical patients in the ALF group with hemodynamic instability and high SOFA scores, so we developed CPDF therapy that can maintain stable hemodynamics in most cases.
We showed CPDF therapy supported liver in this study ,and CPDF therapy also has characteristics of renal replacement therapy.
We previously reported that hepatic function was improved without affecting hemodynamics. Like CHDF therapy, CPDF therapy avoids acute changes and continually removes toxic substances while managing fluid balance(11) .
This helps alleviate pulmonary edema that exacerbates respiratory dysfunction and helps to support liver function(12, 13).
Patients with ALF often have kidney dysfunction. Therefore, CPDF therapy may contribute to improving functions of multiple organs as well as the liver.
Limitations
Several limitations of this study should be acknowledged.
First, this study incorporated a retrospective design and the sample size was small. Second, although not significant, a few patients with conventional therapy underwent CPDF therapy. A randomized controlled study should be needed to compare CPDF therapy with conventional therapy in critical patients with ALF for further analysis. Third, we did not consider other liver function and other severity (e.g. APACHE-Ⅱ).
Conclusion
In conclusion, CPDF therapy had advantages of 14-day and 56-day survival rate, easier preparation and lower dose of FFP compared with conventional therapy. A randomized controlled study should be needed, but it is possible that CPDF therapy can be a new alternative therapy to conventional therapy.